Drug-eluting magnesium(Mg)alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents,demonstrating good clinical efficacy.However,the release of anti-hyperplasia drugs from coa...Drug-eluting magnesium(Mg)alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents,demonstrating good clinical efficacy.However,the release of anti-hyperplasia drugs from coatings delays endothelial tissue repair,thus leading to late stent thrombosis.To address these issues,a dual self-healed coating with various biological properties was fabricated on magnesium fluoride/polydopamine(MgF_(2)/PDA)-treated Mg alloys by spraying-assisted layer-by-layer(LBL)self-assembly of chitosan(CS),gallic acid(GA),and 3-aminobenzeneboronic acid-modified hyaluronic acid(HA-ABBA).The LBL coating,approximately 1.50μm thick,exhibited a uniform morphology with good adhesion strength(~1065 mN).The annual corrosion rate(Pi)of LBL samples was~1400 times slower than that of the Mg substrate,due to the physical barrier function provided by MgF_(2)/PDA layers and the dual self-healed ability of LBL layers.The rapid self-healing ability(with a healing period of~4 h under dynamic/static conditions)resulted from the synergistic interplay between the recombination of diverse chemical bonds within the LBL coating and the coordination of LBL-released GA with Mg2+,as corroborated by computer simulations.Compared with the drug-eluting coatings,the LBL sample demonstrated substantial advantages in anti-oxidation,anti-denaturation of fibrinogen,anti-platelet adhesion,anti-inflammation,anti-hyperplasia,and promoted-endothelialization.These benefits effectively address the limitations associated with drug-eluting coatings.展开更多
Magnesium and its alloy have good mechanical properties and biodegradability,and have become the hotspot of the next-generation biodegradable vascular stent materials.However,their rapid degradation in vivo and poor b...Magnesium and its alloy have good mechanical properties and biodegradability,and have become the hotspot of the next-generation biodegradable vascular stent materials.However,their rapid degradation in vivo and poor biocompatibility are still the bottlenecks of clinical applications for the cardiovascular stents.In particular,how to induce the repair and regeneration of the vascular endothelial with normal physiological functions on the surface of the magnesium alloy stent materials represents the key to its clinical application in the field of cardiovascular stents.It has been believed that it is an ideal way to completely solve the postoperative complications through constructing the multifunctional anti-corrosive bioactive coating on the magnesium alloy surface to induce the formation of vascular endothelium with normal physiological functions.However,how to construct a corrosion-resistant multifunctional bioactive coating with the good endothelial regeneration abilities on the magnesium alloy surface still faces a great challenge.This paper mainly focused on highlighting and summarizing the recent advances in the surface endothelialization of the magnesium alloy materials for the vascular stent,including the bio-inert coating,in-situ immobilization of bioactive molecules on the surface,polymer coating loaded with bioactive factors,novel multifunctional polymer coating,bioactive micropatterns,bioactive layer with glycocalyx-like structure,NO-releasing coating and bioactive sol-gel coating.The advantages and disadvantages of these strategies were discussed and analyzed.Finally,in the senses of future development and clinical application,this paper analyzed and summarized the development direction and prospect of surface endothelialization of the magnesium alloy vascular stents.It is anticipated that this review can give the new cues to the surface endothelialization of the cardiovascular magnesium alloy stents and promote future advancements in this field.展开更多
Rapid formation of a continuous endothelial cell(EC)monolayer with healthy endothelium function on the luminal surface of vascular implants is imperative to improve the longtime patency of small-diameter vascular impl...Rapid formation of a continuous endothelial cell(EC)monolayer with healthy endothelium function on the luminal surface of vascular implants is imperative to improve the longtime patency of small-diameter vascular implants.In the present study,we combined the contact guidance effects of aligned nanofibers,which enhance EC adhesion and proliferation because of its similar fiber scale with native vascular basement membranes,and aligned microfibers,which could induce EC elongation effectively and allow ECs infiltration.It was followed by successive immobilization of collagen IV and laminin to fabricate a biomimetic basement membrane(BBM)with structural and compositional biomimicry.The hemolysis assay and platelet adhesion results showed that the BBM exhibited excellent hemocompatibility.Meanwhile,the adhered human umbilical vein endothelial cells(HUVECs)onto theBBMaligned along the orientation of the microfibers with an elongated morphology,and the data demonstrated that the BBM showed favorable effects on EC attachment,proliferation,and viability.The oriented EC monolayer formed on the BBM exhibited improved antithrombotic capability as indicated by higher production of nitric oxide and prostacyclin(PGI2).Furthermore,fluorescence images indicated that HUVECs could infiltrate into the BBM,implying theBBM’s ability to enhance transmural endothelialization.Hence,theBBMpossessed the properties to regulate ECbehaviors and allow transmural ingrowth,demonstrating the potential to be applied as the luminal surface of small-diameter vascular implants for rapid endothelialization.展开更多
Intracranial vascular stenting has been widely used for ischemic stroke.However,there are complication risks with stent implantation,such as poor wall apposition,stent migration,thromboembolism and stent restenosis,du...Intracranial vascular stenting has been widely used for ischemic stroke.However,there are complication risks with stent implantation,such as poor wall apposition,stent migration,thromboembolism and stent restenosis,due to the mismatched radial force and conformability of the stents."Therefore,a novel intracranial vascular nitinol stent was fabricated in order to improve mechanical property and endothelialization function.The bending moment of the stents was calculated to be 0.346 N mm,which shows improved conformability.The radial force of the stents evaluated by the flat plate test was0.0112 N/mm,within the range of the commercially available stent force(0.0065-0.0116 N/mm).Furthermore,the TyrIle-Gly-Ser-Arg(YIGSR)peptide derived from laminin was grafted onto the stent surfaces to promote endothelialization on vascular stents evaluated by the proliferation,adhesion and migration of human umbilical vein endothelial cells in vitro.The nitinol stents with improved mechanical property and endothelialization function are expected to reduce the recurrence risk of ischemic stroke after implantation.展开更多
Surface endothelialization is a promising way to improve the hemocompatibility of biomaterials.However,current surface endothelialization strategies have limitations.For example,various surface functions are not well ...Surface endothelialization is a promising way to improve the hemocompatibility of biomaterials.However,current surface endothelialization strategies have limitations.For example,various surface functions are not well balanced,leading to undesirable results,especially when multiple functional components are introduced.In this work,a multifunctional surface was constructed by balancing the functions of antifouling,nitric oxide(NO)release and endothelial cell promotion via layer-by-layer(LBL)self-assembly.Poly(sodium p-styrenesulfonate-co-oligo(ethylene glycol)methacrylate)(negatively charged)and polyethyleneimine(positively charged)were deposited on silicon substrates to construct multilayers by LBL self-assembly.Then,organic selenium,which has a NO-releasing function,and the cell-adhesive peptide Gly-Arg-Glu-Asp-Val-Tyr,which selectively promotes endothelial cells,were introduced on the assembled multilayers.Poly(oligo(ethylene glycol)methacrylate)is a hydrophilic component for antifouling properties,and poly(sodium p-styrenesulfonate)is a heparin analog that provides negative charges.By modulating the contents of poly(oligo(ethylene glycol)methacrylate)and poly(sodium p-styrenesulfonate)in the copolymers,the NO release rates catalyzed by the modified surfaces were regulated.Moreover,the behaviors of endothelial cells and smooth muscle cells on modified surfaces were well controlled.The optimized surface strongly promoted endothelial cells and inhibited smooth muscle cells to achieve endothelialization effectively.展开更多
Detection of in vivo biodegradation is critical for development of next-generation medical devices such as bioresorbable stents or scaffolds(BRSs).In particular,it is urgent to establish a nondestructive approach to e...Detection of in vivo biodegradation is critical for development of next-generation medical devices such as bioresorbable stents or scaffolds(BRSs).In particular,it is urgent to establish a nondestructive approach to examine in vivo degradation of a new-generation coronary stent for interventional treatment based on mammal experiments;otherwise it is not available to semi-quantitatively monitor biodegradation in any clinical trial.Herein,we put forward a semi-quantitative approach to measure degradation of a sirolimus-eluting iron bioresorbable scaffold(IBS)based on optical coherence tomography(OCT)images;this approach was confirmed to be consistent with the present weight-loss measurements,which is,however,a destructive approach.The IBS was fabricated by a metal-polymer composite technique with a polylactide coating on an iron stent.The efficacy as a coronary stent of this new bioresorbable scaffold was compared with that of a permanent metal stent with the name of trade mark Xience,which has been widely used in clinic.The endothelial coverage on IBS was found to be greater than on Xience after implantation in a rabbit model;and our well-designed ultrathin stent exhibited less individual variation.We further examined degradation of the IBSs in both minipig coronary artery and rabbit abdominal aorta models.The present result indicated much faster iron degradation of IBS in the rabbit model than in the porcine model.The semi-quantitative approach to detect biodegradation of IBS and the finding of the species difference might be stimulating for fundamental investigation of biodegradable implants and clinical translation of the next-generation coronary stents.展开更多
Vascular diseases are the most prevalent cause of ischemic necrosis of tissue and organ,which even result in dysfunction and death.Vascular regeneration or artificial vascular graft,as the conventional treatment modal...Vascular diseases are the most prevalent cause of ischemic necrosis of tissue and organ,which even result in dysfunction and death.Vascular regeneration or artificial vascular graft,as the conventional treatment modality,has received keen attentions.However,small-diameter(diameter<4 mm)vascular grafts have a high risk of thrombosis and intimal hyperplasia(IH),which makes long-term lumen patency challengeable.Endothelial cells(ECs)form the inner endothelium layer,and are crucial for anti-coagulation and thrombogenesis.Thus,promoting in situ endothelialization in vascular graft remodeling takes top priority,which requires recruitment of endothelia progenitor cells(EPCs),migration,adhesion,proliferation and activation of EPCs and ECs.Chemotaxis aimed at ligands on EPC surface can be utilized for EPC homing,while nanofibrous structure,biocompatible surface and cell-capturing molecules on graft surface can be applied for cell adhesion.Moreover,cell orientation can be regulated by topography of scaffold,and cell bioactivity can be modulated by growth factors and therapeutic genes.Additionally,surface modification can also reduce thrombogenesis,and some drug release can inhibit IH.Considering the influence of macrophages on ECs and smooth muscle cells(SMCs),scaffolds loaded with drugs that can promote M2 polarization are alternative strategies.In conclusion,the advanced strategies for enhanced long-term lumen patency of vascular grafts are summarized in this review.Strategies for recruitment of EPCs,adhesion,proliferation and activation of EPCs and ECs,anti-thrombogenesis,anti-IH,and immunomodulation are discussed.Ideal vascular grafts with appropriate surface modification,loading and fabrication strategies are required in further studies.展开更多
The rapid endothelialization of tissue-engineered blood vessels(TEBVs) can effectively prevent thrombosis and inhibit intimal hyperplasia. The traditional Chinese medicine ingredient icariin is highly promising for th...The rapid endothelialization of tissue-engineered blood vessels(TEBVs) can effectively prevent thrombosis and inhibit intimal hyperplasia. The traditional Chinese medicine ingredient icariin is highly promising for the treatment of cardiovascular diseases.β-cyclodextrin sulfate is a type of hollow molecule that has good biocompatibility and anticoagulation properties and exhibits a sustained release of icariin. We studied whether icariin-loaded β-cyclodextrin sulfate can promote the endothelialization of TEBVs. The experimental results showed that icariin could significantly promote the proliferation and migration of endothelial progenitor cells; at the same time, icariin could promote the migration of rat vascular endothelial cells(RAVECs). Subsequently,we used an electrostatic force to modify the surface of the TEBVs with icariin-loaded β-cyclodextrin sulfate, and these vessels were implanted into the rat common carotid artery. After 3 months, micro-CT results showed that the TEBVs modified using icariin-loaded β-cyclodextrin sulfate had a greater patency rate. Scanning electron microscopy(SEM) and CD31 immunofluorescence results showed a better degree of endothelialization. Taken together, icariin-loaded β-cyclodextrin sulfate can achieve anticoagulation and rapid endothelialization of TEBVs to ensure their long-term patency.展开更多
Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with...Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios,it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization.Herein,on basis of 3D-printed polyelectrolyte-based vascular grafts,a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described.A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles,in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used.Further,dual bioactive molecules,heparin with negative charges and Tyr-Ile-Gly-Ser-Arg(YIGSR)peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes.Due to the electrostatic interaction,the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization.This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction,revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.展开更多
Tissue-engineered vascular grafts(TEVGs)have enormous potential for vascular replacement therapy.However,thrombosis and intimal hyperplasia are important problems associated with TEVGs especially small diameter TEVGs(...Tissue-engineered vascular grafts(TEVGs)have enormous potential for vascular replacement therapy.However,thrombosis and intimal hyperplasia are important problems associated with TEVGs especially small diameter TEVGs(<6 mm)after transplantation.Endothelialization of TEVGs is a key point to prevent thrombosis.Here,we discuss different types of endothelialization and different seed cells of tissue-engineered vascular grafts.Meanwhile,endothelial heterogeneity is also discussed.Based on it,we provide a new perspective for selecting suitable types of endothelialization and suitable seed cells to improve the long-term patency rate of tissue-engineered vascular grafts with different diameters and lengths.展开更多
It is not clear what effects of CD34-and CD133-specific antibody-coated stents have on reendothelialization and in-stent restenosis(ISR)at the early phase of vascular injury.This study aims at determining the capabili...It is not clear what effects of CD34-and CD133-specific antibody-coated stents have on reendothelialization and in-stent restenosis(ISR)at the early phase of vascular injury.This study aims at determining the capabilities of different coatings on stents(e.g.gelatin,anti-CD133 and anti-CD34 antibodies)to promote adhesion and proliferation of endothelial progenitor cells(EPCs).The in vitro study revealed that the adhesion force enabled the EPCs coated on glass slides to withstand flow-induced shear stress,so that allowing for the growth of the cells on the slides for 48 h.The in vivo experiment using a rabbit model in which the coated stents with different substrates were implanted showed that anti-CD34 and anti-CD133 antibody-coated stents markedly reduced the intima area and restenosis than bare mental stents(BMS)and gelatin-coated stents.Compared with the anti-CD34 antibody-coated stents,the time of cells adhesion was longer and earlier present in the anti-CD133 antibody-coated stents and anti-CD133 antibody-coated stents have superiority in re-endothelialization and inhibition of ISR.In conclusion,this study demonstrated that anti-CD133 antibody as a stent coating for capturing EPCs is better than anti-CD34 antibody in promoting endothelialization and reducing ISR.展开更多
Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transana...Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.展开更多
Bioprosthetic heart valve(BHV)replacement has been the predo-minant treatment for severe heart valve diseases over decades.Most clinically available BHVs are crosslinked by glutaraldehyde(GLUT),while the high toxicity...Bioprosthetic heart valve(BHV)replacement has been the predo-minant treatment for severe heart valve diseases over decades.Most clinically available BHVs are crosslinked by glutaraldehyde(GLUT),while the high toxicity of residual GLUT could initiate calcification,severe thrombosis,and delayed endothelializa-tion.Here,we construed a mechanically integrating robust hydrogel-tissue hybrid to improve the performance of BHVs.In particular,recombinant humanized coilagen type Ⅲ(rhCOLⅢ),which was precisely customized with anti-coagulant and pro-endothelialization bioactivity,was first incorporated into the polyvinyl alcohol(PVA)-based hydrogel via hydrogen bond interactions.Then,tannic acid was introduced to enhance the mechanicalperfo of PVA-based hvdrogel and interfacial bonding between the hydrogel layer and bio-derived tissue due to the strong affinity for a wide range of substrates.In vitro and in vivo experimental results confirmed that the GLUT-crosslinked BHVs modified by the robust PVA-based hydrogel embedded rhCOLII and TA possessed long-term anti-coagulant,accelerated endothelialization,mild inflammatory response and anti-calcification properties.Therefore,our mechanically integrating robust hydrogel-tissue hybrid strategy showed the potential to enhance the service function and prolong the service life of the BHVs after implantation.展开更多
In the field of tissue regeneration,the lack of a stable endothelial lining may affect the hemocompatibility of both synthetic and biological replacements.These drawbacks might be prevented by specific biomaterial fun...In the field of tissue regeneration,the lack of a stable endothelial lining may affect the hemocompatibility of both synthetic and biological replacements.These drawbacks might be prevented by specific biomaterial functionalization to induce selective endothelial cell(EC)adhesion.Decellularized bovine pericardia and porcine aortas were selectively functionalized with a REDV tetrapeptide at 10^(-5)M and 10^(-6)M working concentrations.The scaffold-bound peptide was quantified and REDV potential EC adhesion enhancement was evaluated in vitro by static seeding of human umbilical vein ECs.The viable cells and MTS production were statistically higher in functionalized tissues than in control.Scaffold histoarchitecture,geometrical features,and mechanical properties were unaffected by peptide anchoring.The selective immobilization of REDV was effective in accelerating ECs adhesion while promoting proliferation in functionalized decellularized tissues intended for blood-contacting applications.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
OBJECTIVE: To investigate the feasibility of endothelialization of bioprosthesis by transfer of vascular endothelial growth factor (VEGF) gene. METHODS: Bovine pericardium treated with glutaraldehyde and L-glutamic ac...OBJECTIVE: To investigate the feasibility of endothelialization of bioprosthesis by transfer of vascular endothelial growth factor (VEGF) gene. METHODS: Bovine pericardium treated with glutaraldehyde and L-glutamic acid was positioned into the pig right atrium. pcD(2)/hVEGF(121) gene (1 mg) was transferred into the right ventricular myocardium using surgical sutures Reverse transcri ption polymerase chain reaction (RT PCR) was employed to evaluate the expression of myocardial VEGF mRNA. The determination of concentrations of VEGF protein in blood from both the right atrium and peripheral vein, and histological and ultrastructural analysis of implanted bovine pericardium were completed simultaneously. RESULTS: The concentration of VEGF derived from the right atrium in pcD(2)/hVEGF(121) group was significantly higher than that in the pcD(2) group 10 days after VEGF gene transfer (P展开更多
Current gold standard for the replacement of small-diameter blood vessel(ID<4 mm)is still to utilize the autologous vessels of patients due to the limitations of small-diameter vascular grafts(SDVG)on weak endothel...Current gold standard for the replacement of small-diameter blood vessel(ID<4 mm)is still to utilize the autologous vessels of patients due to the limitations of small-diameter vascular grafts(SDVG)on weak endothelialization,intimal hyperplasia and low patency.Herein,we create the SDVG with the tailored endothelialization by applying the engineered endothelial cell vesicles to camouflaging vascular grafts for the enhancement of vascular remodeling.The engineered endothelial cell vesicles were modified with azide groups(ECVs-N3)through metabolic glycoengineering to precisely link the vascular graft made of PCL-DBCO via click chemistry,and thus fabricating ECVG(ECVs-N3 modified SDVG),which assists inhibition of platelet adhesion and activation,promotion of ECs adhesion and enhancement of anti-inflammation.Furthermore,In vivo single-cell transcriptome analysis revealed that the proportion of ECs in the cell composition of ECVG surpassed that of PCL,and the tailored endothelialization enabled to convert endothelial cells(ECs)into some specific ECs clusters.One of the specific cluster,Endo_C5 cluster,was only detected in ECVG.Consequently,our study integrates the engineered membrane vesicles of ECVs-N3 from native ECs for tailored endothelialization on SDVG by circumventing the limitations of living cells,and paves a new way to construct the alternative endothelialization in vessel remodeling following injury.展开更多
Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More r...Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.展开更多
Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the bl...Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the blood–brain barrier undergo morphological and functional transformations.However,the interplay between astrocytes and the blood–brain barrier has received less attention.This comprehensive review explores the physiological and pathological morphological and functional changes in astrocytes and the blood–brain barrier in ischemic stroke.Post-stroke,the structure of endothelial cells and peripheral cells undergoes alterations,causing disruption of the blood–brain barrier.This disruption allows various pro-inflammatory factors and chemokines to cross the blood–brain barrier.Simultaneously,astrocytes swell and primarily adopt two phenotypic states:A1 and A2,which exhibit different roles at different stages of ischemic stroke.During the acute phase,A1 reactive astrocytes secrete vascular endothelial growth factor,matrix metalloproteinases,lipid carrier protein-2,and other cytokines,exacerbating damage to endothelial cells and tight junctions.Conversely,A2 reactive astrocytes produce pentraxin 3,Sonic hedgehog,angiopoietin-1,and other protective factors for endothelial cells.Furthermore,astrocytes indirectly influence blood–brain barrier permeability through ferroptosis and exosomes.In the middle and late(recovery)stages of ischemic stroke,A1 and A2 astrocytes show different effects on glial scar formation.A1 astrocytes promote glial scar formation and inhibit axon growth via glial fibrillary acidic protein,chondroitin sulfate proteoglycans,and transforming growth factor-β.In contrast,A2 astrocytes facilitate axon growth through platelet-derived growth factor,playing a crucial role in vascular remodeling.Therefore,enhancing our understanding of the pathological changes and interactions between astrocytes and the blood–brain barrier is a vital therapeutic target for preventing further brain damage in acute stroke.These insights may pave the way for innovative therapeutic strategies for ischemic stroke.展开更多
基金supported by the National Key Research and Development Program of China(No.2021YFC2400703)the Key Scientific and Technological Research Projects in Henan Province(Nos.232102311155 and 232102230106)Zhengzhou University Major Project Cultivation Special Project(No.125-32214076).
文摘Drug-eluting magnesium(Mg)alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents,demonstrating good clinical efficacy.However,the release of anti-hyperplasia drugs from coatings delays endothelial tissue repair,thus leading to late stent thrombosis.To address these issues,a dual self-healed coating with various biological properties was fabricated on magnesium fluoride/polydopamine(MgF_(2)/PDA)-treated Mg alloys by spraying-assisted layer-by-layer(LBL)self-assembly of chitosan(CS),gallic acid(GA),and 3-aminobenzeneboronic acid-modified hyaluronic acid(HA-ABBA).The LBL coating,approximately 1.50μm thick,exhibited a uniform morphology with good adhesion strength(~1065 mN).The annual corrosion rate(Pi)of LBL samples was~1400 times slower than that of the Mg substrate,due to the physical barrier function provided by MgF_(2)/PDA layers and the dual self-healed ability of LBL layers.The rapid self-healing ability(with a healing period of~4 h under dynamic/static conditions)resulted from the synergistic interplay between the recombination of diverse chemical bonds within the LBL coating and the coordination of LBL-released GA with Mg2+,as corroborated by computer simulations.Compared with the drug-eluting coatings,the LBL sample demonstrated substantial advantages in anti-oxidation,anti-denaturation of fibrinogen,anti-platelet adhesion,anti-inflammation,anti-hyperplasia,and promoted-endothelialization.These benefits effectively address the limitations associated with drug-eluting coatings.
基金financially supported by the National Natural Science Foundation of China(31870952)Natural Science Foundation of Jiangsu Province of China(BK20181480)。
文摘Magnesium and its alloy have good mechanical properties and biodegradability,and have become the hotspot of the next-generation biodegradable vascular stent materials.However,their rapid degradation in vivo and poor biocompatibility are still the bottlenecks of clinical applications for the cardiovascular stents.In particular,how to induce the repair and regeneration of the vascular endothelial with normal physiological functions on the surface of the magnesium alloy stent materials represents the key to its clinical application in the field of cardiovascular stents.It has been believed that it is an ideal way to completely solve the postoperative complications through constructing the multifunctional anti-corrosive bioactive coating on the magnesium alloy surface to induce the formation of vascular endothelium with normal physiological functions.However,how to construct a corrosion-resistant multifunctional bioactive coating with the good endothelial regeneration abilities on the magnesium alloy surface still faces a great challenge.This paper mainly focused on highlighting and summarizing the recent advances in the surface endothelialization of the magnesium alloy materials for the vascular stent,including the bio-inert coating,in-situ immobilization of bioactive molecules on the surface,polymer coating loaded with bioactive factors,novel multifunctional polymer coating,bioactive micropatterns,bioactive layer with glycocalyx-like structure,NO-releasing coating and bioactive sol-gel coating.The advantages and disadvantages of these strategies were discussed and analyzed.Finally,in the senses of future development and clinical application,this paper analyzed and summarized the development direction and prospect of surface endothelialization of the magnesium alloy vascular stents.It is anticipated that this review can give the new cues to the surface endothelialization of the cardiovascular magnesium alloy stents and promote future advancements in this field.
基金This work was supported by the Fundamental Research Funds for the Central Universities(Nos.2232019G-06 and 2232019A3-06)111 project(No.PB0719035)+1 种基金The authors at University of Wisconsin-Madison would like to acknowledge the partial support by the Wisconsin Institute for Discovery(WID),the NHLBI of the National Institutes of Health(No.U01HL134655)the Kuo K.and Cindy F.Wang Professorship.Chenglong Yu also acknowledged the fellowship from the China Scholarship Council(CSC)under the Grant CSC No.201906630070.
文摘Rapid formation of a continuous endothelial cell(EC)monolayer with healthy endothelium function on the luminal surface of vascular implants is imperative to improve the longtime patency of small-diameter vascular implants.In the present study,we combined the contact guidance effects of aligned nanofibers,which enhance EC adhesion and proliferation because of its similar fiber scale with native vascular basement membranes,and aligned microfibers,which could induce EC elongation effectively and allow ECs infiltration.It was followed by successive immobilization of collagen IV and laminin to fabricate a biomimetic basement membrane(BBM)with structural and compositional biomimicry.The hemolysis assay and platelet adhesion results showed that the BBM exhibited excellent hemocompatibility.Meanwhile,the adhered human umbilical vein endothelial cells(HUVECs)onto theBBMaligned along the orientation of the microfibers with an elongated morphology,and the data demonstrated that the BBM showed favorable effects on EC attachment,proliferation,and viability.The oriented EC monolayer formed on the BBM exhibited improved antithrombotic capability as indicated by higher production of nitric oxide and prostacyclin(PGI2).Furthermore,fluorescence images indicated that HUVECs could infiltrate into the BBM,implying theBBM’s ability to enhance transmural endothelialization.Hence,theBBMpossessed the properties to regulate ECbehaviors and allow transmural ingrowth,demonstrating the potential to be applied as the luminal surface of small-diameter vascular implants for rapid endothelialization.
基金financially supported by the National Key Research and Development program(No.2018YFC1105503)。
文摘Intracranial vascular stenting has been widely used for ischemic stroke.However,there are complication risks with stent implantation,such as poor wall apposition,stent migration,thromboembolism and stent restenosis,due to the mismatched radial force and conformability of the stents."Therefore,a novel intracranial vascular nitinol stent was fabricated in order to improve mechanical property and endothelialization function.The bending moment of the stents was calculated to be 0.346 N mm,which shows improved conformability.The radial force of the stents evaluated by the flat plate test was0.0112 N/mm,within the range of the commercially available stent force(0.0065-0.0116 N/mm).Furthermore,the TyrIle-Gly-Ser-Arg(YIGSR)peptide derived from laminin was grafted onto the stent surfaces to promote endothelialization on vascular stents evaluated by the proliferation,adhesion and migration of human umbilical vein endothelial cells in vitro.The nitinol stents with improved mechanical property and endothelialization function are expected to reduce the recurrence risk of ischemic stroke after implantation.
基金supported primarily by the National Natural Science Foundation of China(22075191,21774089,and 21935008)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)+1 种基金the Key Laboratory of Polymeric Materials Design and Synthesis for Biomedical Function,Soochow Universitythe Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application,Soochow University.
文摘Surface endothelialization is a promising way to improve the hemocompatibility of biomaterials.However,current surface endothelialization strategies have limitations.For example,various surface functions are not well balanced,leading to undesirable results,especially when multiple functional components are introduced.In this work,a multifunctional surface was constructed by balancing the functions of antifouling,nitric oxide(NO)release and endothelial cell promotion via layer-by-layer(LBL)self-assembly.Poly(sodium p-styrenesulfonate-co-oligo(ethylene glycol)methacrylate)(negatively charged)and polyethyleneimine(positively charged)were deposited on silicon substrates to construct multilayers by LBL self-assembly.Then,organic selenium,which has a NO-releasing function,and the cell-adhesive peptide Gly-Arg-Glu-Asp-Val-Tyr,which selectively promotes endothelial cells,were introduced on the assembled multilayers.Poly(oligo(ethylene glycol)methacrylate)is a hydrophilic component for antifouling properties,and poly(sodium p-styrenesulfonate)is a heparin analog that provides negative charges.By modulating the contents of poly(oligo(ethylene glycol)methacrylate)and poly(sodium p-styrenesulfonate)in the copolymers,the NO release rates catalyzed by the modified surfaces were regulated.Moreover,the behaviors of endothelial cells and smooth muscle cells on modified surfaces were well controlled.The optimized surface strongly promoted endothelial cells and inhibited smooth muscle cells to achieve endothelialization effectively.
基金National Key R&D Program of China(grants number 2018YFC1106600 and 2016YFC1100300)Shenzhen Industrial and Information Technology Bureau(20180309174916657)+1 种基金Science,Technology and Innovation Commission of Shenzhen Municipality(grant number GJHZ20180418190517302)The authors thank Dr.Renu Virmani for her expert assistance on endothelialization and histopathology analysis.
文摘Detection of in vivo biodegradation is critical for development of next-generation medical devices such as bioresorbable stents or scaffolds(BRSs).In particular,it is urgent to establish a nondestructive approach to examine in vivo degradation of a new-generation coronary stent for interventional treatment based on mammal experiments;otherwise it is not available to semi-quantitatively monitor biodegradation in any clinical trial.Herein,we put forward a semi-quantitative approach to measure degradation of a sirolimus-eluting iron bioresorbable scaffold(IBS)based on optical coherence tomography(OCT)images;this approach was confirmed to be consistent with the present weight-loss measurements,which is,however,a destructive approach.The IBS was fabricated by a metal-polymer composite technique with a polylactide coating on an iron stent.The efficacy as a coronary stent of this new bioresorbable scaffold was compared with that of a permanent metal stent with the name of trade mark Xience,which has been widely used in clinic.The endothelial coverage on IBS was found to be greater than on Xience after implantation in a rabbit model;and our well-designed ultrathin stent exhibited less individual variation.We further examined degradation of the IBSs in both minipig coronary artery and rabbit abdominal aorta models.The present result indicated much faster iron degradation of IBS in the rabbit model than in the porcine model.The semi-quantitative approach to detect biodegradation of IBS and the finding of the species difference might be stimulating for fundamental investigation of biodegradable implants and clinical translation of the next-generation coronary stents.
基金This work was funded by the National Natural Science Foundation of China(82072396,81871490,81571022)Shanghai Collaborative Innovation Center for Translational Medicine(TM202010)+2 种基金Program of Shanghai Academic/Technology Research Leader(19XD1434500)Double Hundred Plan(20191819)the Research Fund of Medicine and Engineering of Shanghai Jiao Tong University(YG2017MS06).
文摘Vascular diseases are the most prevalent cause of ischemic necrosis of tissue and organ,which even result in dysfunction and death.Vascular regeneration or artificial vascular graft,as the conventional treatment modality,has received keen attentions.However,small-diameter(diameter<4 mm)vascular grafts have a high risk of thrombosis and intimal hyperplasia(IH),which makes long-term lumen patency challengeable.Endothelial cells(ECs)form the inner endothelium layer,and are crucial for anti-coagulation and thrombogenesis.Thus,promoting in situ endothelialization in vascular graft remodeling takes top priority,which requires recruitment of endothelia progenitor cells(EPCs),migration,adhesion,proliferation and activation of EPCs and ECs.Chemotaxis aimed at ligands on EPC surface can be utilized for EPC homing,while nanofibrous structure,biocompatible surface and cell-capturing molecules on graft surface can be applied for cell adhesion.Moreover,cell orientation can be regulated by topography of scaffold,and cell bioactivity can be modulated by growth factors and therapeutic genes.Additionally,surface modification can also reduce thrombogenesis,and some drug release can inhibit IH.Considering the influence of macrophages on ECs and smooth muscle cells(SMCs),scaffolds loaded with drugs that can promote M2 polarization are alternative strategies.In conclusion,the advanced strategies for enhanced long-term lumen patency of vascular grafts are summarized in this review.Strategies for recruitment of EPCs,adhesion,proliferation and activation of EPCs and ECs,anti-thrombogenesis,anti-IH,and immunomodulation are discussed.Ideal vascular grafts with appropriate surface modification,loading and fabrication strategies are required in further studies.
基金supported by the National Science Fund for Distinguished Young Scholars (31625011)the National Key Research and Development Program (2016YFC1101100)+1 种基金the National Key Research and Development Plan Young Scientists Program (2017YFA0106000)the Young Elite Scientists Sponsorship Program by Cast (YESS20160180)
文摘The rapid endothelialization of tissue-engineered blood vessels(TEBVs) can effectively prevent thrombosis and inhibit intimal hyperplasia. The traditional Chinese medicine ingredient icariin is highly promising for the treatment of cardiovascular diseases.β-cyclodextrin sulfate is a type of hollow molecule that has good biocompatibility and anticoagulation properties and exhibits a sustained release of icariin. We studied whether icariin-loaded β-cyclodextrin sulfate can promote the endothelialization of TEBVs. The experimental results showed that icariin could significantly promote the proliferation and migration of endothelial progenitor cells; at the same time, icariin could promote the migration of rat vascular endothelial cells(RAVECs). Subsequently,we used an electrostatic force to modify the surface of the TEBVs with icariin-loaded β-cyclodextrin sulfate, and these vessels were implanted into the rat common carotid artery. After 3 months, micro-CT results showed that the TEBVs modified using icariin-loaded β-cyclodextrin sulfate had a greater patency rate. Scanning electron microscopy(SEM) and CD31 immunofluorescence results showed a better degree of endothelialization. Taken together, icariin-loaded β-cyclodextrin sulfate can achieve anticoagulation and rapid endothelialization of TEBVs to ensure their long-term patency.
基金The authors gratefully acknowledge the support for this work from the National Key research and Development Program(Grant No.2018YFA0703100)the National Natural Science Foundation of China(Grant Nos.82072082,31900959)+2 种基金the Youth Innovation Promotion Association of CAS(Grant No.2019350)the Guangdong Natural Science Foundation(Grant No.2019A1515011277)the Shenzhen Fundamental Research Foundation(Grant No.JCYJ20180507182237428).
文摘Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios,it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization.Herein,on basis of 3D-printed polyelectrolyte-based vascular grafts,a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described.A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles,in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used.Further,dual bioactive molecules,heparin with negative charges and Tyr-Ile-Gly-Ser-Arg(YIGSR)peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes.Due to the electrostatic interaction,the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization.This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction,revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.
基金supported by The National Science Fund for Outstanding Young Scholars(No:31822021)The Key Research and Development Plan Young Scientists Program(No:2017YFA0106000)+1 种基金The National Key Research and Development Plan(No:2016YFC1101100)National Science Foundation of China(No:31771057).
文摘Tissue-engineered vascular grafts(TEVGs)have enormous potential for vascular replacement therapy.However,thrombosis and intimal hyperplasia are important problems associated with TEVGs especially small diameter TEVGs(<6 mm)after transplantation.Endothelialization of TEVGs is a key point to prevent thrombosis.Here,we discuss different types of endothelialization and different seed cells of tissue-engineered vascular grafts.Meanwhile,endothelial heterogeneity is also discussed.Based on it,we provide a new perspective for selecting suitable types of endothelialization and suitable seed cells to improve the long-term patency rate of tissue-engineered vascular grafts with different diameters and lengths.
基金This study was partially supported by grants-in-aid from the National Natural Science Foundation of China(11332003,31370949)the National Key Technology R&D Program of China(2012BAI18B02)the National Key Basic Research Program of China(2012CB619101)。
文摘It is not clear what effects of CD34-and CD133-specific antibody-coated stents have on reendothelialization and in-stent restenosis(ISR)at the early phase of vascular injury.This study aims at determining the capabilities of different coatings on stents(e.g.gelatin,anti-CD133 and anti-CD34 antibodies)to promote adhesion and proliferation of endothelial progenitor cells(EPCs).The in vitro study revealed that the adhesion force enabled the EPCs coated on glass slides to withstand flow-induced shear stress,so that allowing for the growth of the cells on the slides for 48 h.The in vivo experiment using a rabbit model in which the coated stents with different substrates were implanted showed that anti-CD34 and anti-CD133 antibody-coated stents markedly reduced the intima area and restenosis than bare mental stents(BMS)and gelatin-coated stents.Compared with the anti-CD34 antibody-coated stents,the time of cells adhesion was longer and earlier present in the anti-CD133 antibody-coated stents and anti-CD133 antibody-coated stents have superiority in re-endothelialization and inhibition of ISR.In conclusion,this study demonstrated that anti-CD133 antibody as a stent coating for capturing EPCs is better than anti-CD34 antibody in promoting endothelialization and reducing ISR.
基金This work was supported by the National Institutes of Health grants[NIH R01HL130274 and R01HL144113]NSERC-CREATE Training in Global Biomedical Technology Research and Innovation at the University of Waterloo[CREATE-509950-2018]+2 种基金Canada Foundation for Innovation(CFI35573)NSERC Research Tools and Instruments Fund(RTI-2018-00220)the Oregon National Primate Research Center NIH grant award[P51OD011092].
文摘Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.
基金supported by National Key Research and Development Programs(2022YFB3807303 and 2022YFB3807305),National Natural Science Foundation of China(32101107)and CAMS InnovationFundforMedical Sciences(2021-12M-5-013)。
文摘Bioprosthetic heart valve(BHV)replacement has been the predo-minant treatment for severe heart valve diseases over decades.Most clinically available BHVs are crosslinked by glutaraldehyde(GLUT),while the high toxicity of residual GLUT could initiate calcification,severe thrombosis,and delayed endothelializa-tion.Here,we construed a mechanically integrating robust hydrogel-tissue hybrid to improve the performance of BHVs.In particular,recombinant humanized coilagen type Ⅲ(rhCOLⅢ),which was precisely customized with anti-coagulant and pro-endothelialization bioactivity,was first incorporated into the polyvinyl alcohol(PVA)-based hydrogel via hydrogen bond interactions.Then,tannic acid was introduced to enhance the mechanicalperfo of PVA-based hvdrogel and interfacial bonding between the hydrogel layer and bio-derived tissue due to the strong affinity for a wide range of substrates.In vitro and in vivo experimental results confirmed that the GLUT-crosslinked BHVs modified by the robust PVA-based hydrogel embedded rhCOLII and TA possessed long-term anti-coagulant,accelerated endothelialization,mild inflammatory response and anti-calcification properties.Therefore,our mechanically integrating robust hydrogel-tissue hybrid strategy showed the potential to enhance the service function and prolong the service life of the BHVs after implantation.
基金Padua Heart Program(CA.RI.PA.RO.Foundation)LIFELAB Program,Consorzio per la Ricerca Sanitaria-CORIS,Veneto Region,Via Giustiniani,2-Padova+1 种基金JLGR acknowledges financial support from the Spanish State Research Agency(AEI)through the PID2019-106099RB-C41/AEI/10.13039/501100011033 projectCIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011,Iniciativa Ingenio 2010,Consolider Program.CIBER Actions are financed by the Instituto de Salud CarlosⅢwith assistance from the European Regional Development Fund.
文摘In the field of tissue regeneration,the lack of a stable endothelial lining may affect the hemocompatibility of both synthetic and biological replacements.These drawbacks might be prevented by specific biomaterial functionalization to induce selective endothelial cell(EC)adhesion.Decellularized bovine pericardia and porcine aortas were selectively functionalized with a REDV tetrapeptide at 10^(-5)M and 10^(-6)M working concentrations.The scaffold-bound peptide was quantified and REDV potential EC adhesion enhancement was evaluated in vitro by static seeding of human umbilical vein ECs.The viable cells and MTS production were statistically higher in functionalized tissues than in control.Scaffold histoarchitecture,geometrical features,and mechanical properties were unaffected by peptide anchoring.The selective immobilization of REDV was effective in accelerating ECs adhesion while promoting proliferation in functionalized decellularized tissues intended for blood-contacting applications.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金agrantfromtheEducationAssociationofJiangsuProvince ,China (No .98JKB32 0 0 0 8)
文摘OBJECTIVE: To investigate the feasibility of endothelialization of bioprosthesis by transfer of vascular endothelial growth factor (VEGF) gene. METHODS: Bovine pericardium treated with glutaraldehyde and L-glutamic acid was positioned into the pig right atrium. pcD(2)/hVEGF(121) gene (1 mg) was transferred into the right ventricular myocardium using surgical sutures Reverse transcri ption polymerase chain reaction (RT PCR) was employed to evaluate the expression of myocardial VEGF mRNA. The determination of concentrations of VEGF protein in blood from both the right atrium and peripheral vein, and histological and ultrastructural analysis of implanted bovine pericardium were completed simultaneously. RESULTS: The concentration of VEGF derived from the right atrium in pcD(2)/hVEGF(121) group was significantly higher than that in the pcD(2) group 10 days after VEGF gene transfer (P
基金National Key Research and Development Program of China(2022YFA1105100)National Natural Science Foundation of China(32301102+3 种基金32171323)Fundamental Research Funds for the Central Universities(YCJJ20230215)Science,Technology and Innovation Commission of Shenzhen Municipality(KCXFZ20211020164544008)Sanming Project of Medicine in Shenzhen(SZSM201812055).
文摘Current gold standard for the replacement of small-diameter blood vessel(ID<4 mm)is still to utilize the autologous vessels of patients due to the limitations of small-diameter vascular grafts(SDVG)on weak endothelialization,intimal hyperplasia and low patency.Herein,we create the SDVG with the tailored endothelialization by applying the engineered endothelial cell vesicles to camouflaging vascular grafts for the enhancement of vascular remodeling.The engineered endothelial cell vesicles were modified with azide groups(ECVs-N3)through metabolic glycoengineering to precisely link the vascular graft made of PCL-DBCO via click chemistry,and thus fabricating ECVG(ECVs-N3 modified SDVG),which assists inhibition of platelet adhesion and activation,promotion of ECs adhesion and enhancement of anti-inflammation.Furthermore,In vivo single-cell transcriptome analysis revealed that the proportion of ECs in the cell composition of ECVG surpassed that of PCL,and the tailored endothelialization enabled to convert endothelial cells(ECs)into some specific ECs clusters.One of the specific cluster,Endo_C5 cluster,was only detected in ECVG.Consequently,our study integrates the engineered membrane vesicles of ECVs-N3 from native ECs for tailored endothelialization on SDVG by circumventing the limitations of living cells,and paves a new way to construct the alternative endothelialization in vessel remodeling following injury.
基金supported by the National Natural Science Foundation of China,Nos.82404892(to QY),82061160374(to ZZ)the Science and Technology Development Fund,Macao Special Administrative Region,China,Nos.0023/2020/AFJ,0035/2020/AGJ+2 种基金the University of Macao Research Grant,Nos.MYRG2022-00248-ICMS,MYRG-CRG2022-00010-ICMS(to MPMH)the Natural Science Foundation of Guangdong Province,No.2024A1515012818(to ZZ)the Fundamental Research Funds for the Central Universities,No.21623114(to ZZ).
文摘Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.
基金supported by the National Natural Science Foundation of China,No.U21A20400(to QW)the National Natural Science Foundation of China,No.82104560(to CL)+1 种基金the Natural Science Foundation of Beijing,No.7232279(to XW)the Project of Beijing University of Chinese Medicine,Nos.2024-JYB-JBZD-043(to CL),2022-JYB-JBZR-004(to XW)。
文摘Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the blood–brain barrier undergo morphological and functional transformations.However,the interplay between astrocytes and the blood–brain barrier has received less attention.This comprehensive review explores the physiological and pathological morphological and functional changes in astrocytes and the blood–brain barrier in ischemic stroke.Post-stroke,the structure of endothelial cells and peripheral cells undergoes alterations,causing disruption of the blood–brain barrier.This disruption allows various pro-inflammatory factors and chemokines to cross the blood–brain barrier.Simultaneously,astrocytes swell and primarily adopt two phenotypic states:A1 and A2,which exhibit different roles at different stages of ischemic stroke.During the acute phase,A1 reactive astrocytes secrete vascular endothelial growth factor,matrix metalloproteinases,lipid carrier protein-2,and other cytokines,exacerbating damage to endothelial cells and tight junctions.Conversely,A2 reactive astrocytes produce pentraxin 3,Sonic hedgehog,angiopoietin-1,and other protective factors for endothelial cells.Furthermore,astrocytes indirectly influence blood–brain barrier permeability through ferroptosis and exosomes.In the middle and late(recovery)stages of ischemic stroke,A1 and A2 astrocytes show different effects on glial scar formation.A1 astrocytes promote glial scar formation and inhibit axon growth via glial fibrillary acidic protein,chondroitin sulfate proteoglycans,and transforming growth factor-β.In contrast,A2 astrocytes facilitate axon growth through platelet-derived growth factor,playing a crucial role in vascular remodeling.Therefore,enhancing our understanding of the pathological changes and interactions between astrocytes and the blood–brain barrier is a vital therapeutic target for preventing further brain damage in acute stroke.These insights may pave the way for innovative therapeutic strategies for ischemic stroke.
