Endothelial cells(ECs)not only serve as a barrier between blood and extravascular space to modulate the exchange of fluid,macromolecules and cells,but also play a critical role in regulation of vascular homeostasis an...Endothelial cells(ECs)not only serve as a barrier between blood and extravascular space to modulate the exchange of fluid,macromolecules and cells,but also play a critical role in regulation of vascular homeostasis and adaptation under mechanical stimulus via intrinsic mechanotransduction.Recently,with the dissection of microdomains responsible for cellular responsiveness to mechanical stimulus,a lot of mechanosensing molecules(mechanosensors)and pathways have been identified in ECs.In addition,there is growing evidence that endothelial mechanosensors not only serve as key vascular gatekeepers,but also contribute to the pathogenesis of various vascular disorders.This review focuses on recent findings in endothelial mechanosensors in subcellular microdomains and their roles in regulation of physiological and pathological functions under mechanical stress.展开更多
Mechanosensors,as the core component of a proprioceptive system,can detect many types of mechanical signals in their surroundings,such as force signals,displacement signals,and vibration signals.It is understandable t...Mechanosensors,as the core component of a proprioceptive system,can detect many types of mechanical signals in their surroundings,such as force signals,displacement signals,and vibration signals.It is understandable that the development of an all-new mechanosensory structure that can be widely used is highly desirable.This is because it can markedly improve the detection performance of mechanosensors.Coincidentally,in nature,optimized microscale trigger hairs of Venus flytrap are ingeniously used as a mechanosensory structure.These trigger hairs are utilized for tactile mechanosensilla to efficiently detect external mechanical stimuli.Biological trigger hair-based mechanosensilla offer an all-new bio-inspired strategy.This strategy utilizes the notch structure and variable stiffness to enhance the perceptual performance of mechanosensors.In this study,the structure-performance-application coupling relationship of trigger hair-based mechanosensors is explored through experiment and analysis.An artificial trigger hair-based mechanosensor is developed by mimicking the deformation properties of the Venus flytrap trigger hair.This bio-inspired mechanosensor shows excellent performance in terms of mechanical stability,response time,and sensitivity to mechanical signals.展开更多
Cells are exposed to various mechanical forces,including extracellular and intracellular forces such as stiffness,tension,compression,viscosity,and shear stress,which regulate cell biology.The process of transducing m...Cells are exposed to various mechanical forces,including extracellular and intracellular forces such as stiffness,tension,compression,viscosity,and shear stress,which regulate cell biology.The process of transducing mechanical stimuli into biochemical signals is termed mechanotransduction.These mechanical forces can regulate protein and gene expression,thereby impacting cell morphology,adhesion,proliferation,apoptosis,and migration.During cancer development,significant changes in extracellular and intracellular mechanical properties occur,resulting in altered mechanical inputs to which cells are exposed.MicroRNAs(miRNAs),key post-transcriptional regulators of gene and protein expression,are increasingly recognized as mechanosensitive molecules involved in cancer development.In this review,we summarize the primary cellular pathways involved in force sensing and mechanotransduction,emphasizing the role of forces in miRNA biogenesis and expression,as well as their influence on the regulation of key mechanotransducers.Furthermore,we focus on recent evidence regarding the induction or repression of miRNAs involved in cancer development by mechanical forces and their impact on the regulation of proteins that contribute to cancer progression.展开更多
Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertensio...Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.展开更多
Introduction Primary cilium is a non-motile microstructure,protruding from cell surface of most mammalian cells.It was previously thought to be vestigial.However,recent studies indicate that it may serve as one of the...Introduction Primary cilium is a non-motile microstructure,protruding from cell surface of most mammalian cells.It was previously thought to be vestigial.However,recent studies indicate that it may serve as one of the most vital mechanosensors for many types of cells such as epithelial and endothelial cells and osteocytes.Protruding from the apical membrane,the primary cilium can directly sense subtle variation of mechanical forces exerted on the cell and then transduce the mechanical cues into biochemical signals into the cell,although the mechanism remain elusive.Vascular endothelial cells(ECs)lining the inner wall of our blood vessels are continuously exposed to the blood flow.In order to maintain proper functions for the cardiovascular system,ECs should have a variety of mechano-sensors and transducers to sense the blood flow change and adjust the vessel size and transport across the vessel wall accordingly.Among more than a dozen recognized EC mechano-sensors,the primary cilium has drawn more and more attention recently.Primary cilium on endothelial cells is essential for the homeostasis of vessels.It is reported to be prevalent in areas of disturbed flow where atherosclerosis and intracranial aneurysm usually occur.Deficiencies of primary cilia may promote atherosclerosis,endothelial-to-mesenchymal transition(EndoMT)and loss of direction orientation,to name a few.Therefore understanding why the primary cilia are necessary to maintain the homeostasis of blood vessels and how will help us develop better treatment strategies for the common cardiovascular diseases.Dimension and structure of primary cilium Primary cilium is reported to be shorter than 8 in length and about 0.2 in diameter.The length of primary cilium varies in different cell types and under different conditions.The major structural components of the primary cilium include basal body,ciliary axoneme(consisting of nine doublet microtubules),ciliary membrane,transition zone,basal feet,and striated rootlets.Each part of the primary cilium is essential and has specific function.Current methods investigating the EC primary cilium as a mechano-sensor:Immunostaining and imaging techniques have been used to investigate the molecular mechanisms by which EC primary cilium serves as a mechano-sensor and transducer.It has been found that various proteins locate on the primary cilium,working together to maintain the function of primary cilium.Some proteins function as ion-channels,mediating Ca2+entry into the primary cilium.Some are involved in the cascade signal pathway.Others are related to the assembly and maintenance of primary cilium.Briefly,the flow induces the deflection of the EC primary cilium,which triggers calcium increase via opening of the PC2 cation channel that is responsible for calcium ion influx.This PC2 cation channel is localized to the primary cilium and is assumed to be stretch-activated.The resulting change in the intracellular calcium concentration then regulates numerous molecular activities inside the cell that contribute to vessel homeostasis.In addition to triggering calcium release,another mechanism has also been found in blood-pressure maintenance in the vasculature,where the vessel diameter is regulated by endothelial primary cilia through adjusting nitric oxide production.So far,little is known about the mechanical mechanism behind this deflection-triggered o-pening of signaling pathways.For example,what is the flow induced bending behavior and force distribution? What is the threshold value of stretch/defection for activating a corresponding signaling pathway? These all remain to be answered.In combination of image data and experiments,several computational models have been established to answer these questions.However,the current models are not able to include the complex structure of primary cilium and the model predictions are limited.Future studies With the development of super high resolution optical microscopy,more detailed images for the structural(molecular)components of EC primary cilia will be revealed,especially when the ECs are alive and the forces are known.Combining these experimental observations with more sophisticated mathematical models will elucidate the mechano-sensing mechanism of EC primary cilia,as the force and stress distribution on cilium along with other mechanical properties are still beyond the capability of experimental approaches due to the scales of the quantities involved.By using numerical approaches,much more detailed dynamic information can be obtained.展开更多
基金supported by the National Natural Science Foundation of China(91339111,31221002)National Basic Research Program of China(2012CB945100)to Luo JinCai
文摘Endothelial cells(ECs)not only serve as a barrier between blood and extravascular space to modulate the exchange of fluid,macromolecules and cells,but also play a critical role in regulation of vascular homeostasis and adaptation under mechanical stimulus via intrinsic mechanotransduction.Recently,with the dissection of microdomains responsible for cellular responsiveness to mechanical stimulus,a lot of mechanosensing molecules(mechanosensors)and pathways have been identified in ECs.In addition,there is growing evidence that endothelial mechanosensors not only serve as key vascular gatekeepers,but also contribute to the pathogenesis of various vascular disorders.This review focuses on recent findings in endothelial mechanosensors in subcellular microdomains and their roles in regulation of physiological and pathological functions under mechanical stress.
基金supported by the National Natural Science Foundation of China(Grant nos.52005355 and 52005356)the Natural Science Foundation of Jiangsu Province(BK2020881).
文摘Mechanosensors,as the core component of a proprioceptive system,can detect many types of mechanical signals in their surroundings,such as force signals,displacement signals,and vibration signals.It is understandable that the development of an all-new mechanosensory structure that can be widely used is highly desirable.This is because it can markedly improve the detection performance of mechanosensors.Coincidentally,in nature,optimized microscale trigger hairs of Venus flytrap are ingeniously used as a mechanosensory structure.These trigger hairs are utilized for tactile mechanosensilla to efficiently detect external mechanical stimuli.Biological trigger hair-based mechanosensilla offer an all-new bio-inspired strategy.This strategy utilizes the notch structure and variable stiffness to enhance the perceptual performance of mechanosensors.In this study,the structure-performance-application coupling relationship of trigger hair-based mechanosensors is explored through experiment and analysis.An artificial trigger hair-based mechanosensor is developed by mimicking the deformation properties of the Venus flytrap trigger hair.This bio-inspired mechanosensor shows excellent performance in terms of mechanical stability,response time,and sensitivity to mechanical signals.
文摘Cells are exposed to various mechanical forces,including extracellular and intracellular forces such as stiffness,tension,compression,viscosity,and shear stress,which regulate cell biology.The process of transducing mechanical stimuli into biochemical signals is termed mechanotransduction.These mechanical forces can regulate protein and gene expression,thereby impacting cell morphology,adhesion,proliferation,apoptosis,and migration.During cancer development,significant changes in extracellular and intracellular mechanical properties occur,resulting in altered mechanical inputs to which cells are exposed.MicroRNAs(miRNAs),key post-transcriptional regulators of gene and protein expression,are increasingly recognized as mechanosensitive molecules involved in cancer development.In this review,we summarize the primary cellular pathways involved in force sensing and mechanotransduction,emphasizing the role of forces in miRNA biogenesis and expression,as well as their influence on the regulation of key mechanotransducers.Furthermore,we focus on recent evidence regarding the induction or repression of miRNAs involved in cancer development by mechanical forces and their impact on the regulation of proteins that contribute to cancer progression.
文摘Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.
基金supported by grants ( 11421202,11572029) from National Natural Science Foundation of China
文摘Introduction Primary cilium is a non-motile microstructure,protruding from cell surface of most mammalian cells.It was previously thought to be vestigial.However,recent studies indicate that it may serve as one of the most vital mechanosensors for many types of cells such as epithelial and endothelial cells and osteocytes.Protruding from the apical membrane,the primary cilium can directly sense subtle variation of mechanical forces exerted on the cell and then transduce the mechanical cues into biochemical signals into the cell,although the mechanism remain elusive.Vascular endothelial cells(ECs)lining the inner wall of our blood vessels are continuously exposed to the blood flow.In order to maintain proper functions for the cardiovascular system,ECs should have a variety of mechano-sensors and transducers to sense the blood flow change and adjust the vessel size and transport across the vessel wall accordingly.Among more than a dozen recognized EC mechano-sensors,the primary cilium has drawn more and more attention recently.Primary cilium on endothelial cells is essential for the homeostasis of vessels.It is reported to be prevalent in areas of disturbed flow where atherosclerosis and intracranial aneurysm usually occur.Deficiencies of primary cilia may promote atherosclerosis,endothelial-to-mesenchymal transition(EndoMT)and loss of direction orientation,to name a few.Therefore understanding why the primary cilia are necessary to maintain the homeostasis of blood vessels and how will help us develop better treatment strategies for the common cardiovascular diseases.Dimension and structure of primary cilium Primary cilium is reported to be shorter than 8 in length and about 0.2 in diameter.The length of primary cilium varies in different cell types and under different conditions.The major structural components of the primary cilium include basal body,ciliary axoneme(consisting of nine doublet microtubules),ciliary membrane,transition zone,basal feet,and striated rootlets.Each part of the primary cilium is essential and has specific function.Current methods investigating the EC primary cilium as a mechano-sensor:Immunostaining and imaging techniques have been used to investigate the molecular mechanisms by which EC primary cilium serves as a mechano-sensor and transducer.It has been found that various proteins locate on the primary cilium,working together to maintain the function of primary cilium.Some proteins function as ion-channels,mediating Ca2+entry into the primary cilium.Some are involved in the cascade signal pathway.Others are related to the assembly and maintenance of primary cilium.Briefly,the flow induces the deflection of the EC primary cilium,which triggers calcium increase via opening of the PC2 cation channel that is responsible for calcium ion influx.This PC2 cation channel is localized to the primary cilium and is assumed to be stretch-activated.The resulting change in the intracellular calcium concentration then regulates numerous molecular activities inside the cell that contribute to vessel homeostasis.In addition to triggering calcium release,another mechanism has also been found in blood-pressure maintenance in the vasculature,where the vessel diameter is regulated by endothelial primary cilia through adjusting nitric oxide production.So far,little is known about the mechanical mechanism behind this deflection-triggered o-pening of signaling pathways.For example,what is the flow induced bending behavior and force distribution? What is the threshold value of stretch/defection for activating a corresponding signaling pathway? These all remain to be answered.In combination of image data and experiments,several computational models have been established to answer these questions.However,the current models are not able to include the complex structure of primary cilium and the model predictions are limited.Future studies With the development of super high resolution optical microscopy,more detailed images for the structural(molecular)components of EC primary cilia will be revealed,especially when the ECs are alive and the forces are known.Combining these experimental observations with more sophisticated mathematical models will elucidate the mechano-sensing mechanism of EC primary cilia,as the force and stress distribution on cilium along with other mechanical properties are still beyond the capability of experimental approaches due to the scales of the quantities involved.By using numerical approaches,much more detailed dynamic information can be obtained.
基金Research from the corresponding author’s laboratory was supported by the National Natural Science Foundation of China(No.91949112,81974052,91939302,and 81921001)。
