Mitochondrial transplantation promotes cardiac repair following injury;however,its effects on limb ischemia due to peripheral artery disease(PAD)remain unclear.In this study,transplantation with mitochondria isolated ...Mitochondrial transplantation promotes cardiac repair following injury;however,its effects on limb ischemia due to peripheral artery disease(PAD)remain unclear.In this study,transplantation with mitochondria isolated from both murine muscle tissue and human arterial blood significantly promotes revascularization and blood flow recovery in a hindlimb ischemia mouse model.Our findings further show that transplanted mitochondria promote macrophages infiltrating into ischemic regions.Additionally,internalization of the mitochondria promotes macrophage M2-like polarization,resulting in increased pro-angiogenic factors expression and secretion and subsequent endothelial cell and smooth muscle cell proliferation.In conclusion,mitochondrial transplantation shows considerable potential in improving peripheral ischemia and provides therapeutic options for patients with PAD.展开更多
EphrinB2(erythropoietin-producing hepatoma interactor B2)is a key Eph/ephrin family member,promoting angiogenesis,vasculogenesis,and lymphangiogenesis during embryonic development.However,the role of EphrinB2 in cardi...EphrinB2(erythropoietin-producing hepatoma interactor B2)is a key Eph/ephrin family member,promoting angiogenesis,vasculogenesis,and lymphangiogenesis during embryonic development.However,the role of EphrinB2 in cardiac lymphangiogenesis following myocardial infarction(MI)and the potential molecular mechanism remains to be demonstrated.This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway.Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI.At the same time,overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart.The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in Lyve1 knockout mice.Mechanistically,EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation.EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3(FLT4)promoter,and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function.We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.展开更多
基金supported by grants from the National Natural Science Foundation of China(82270264,T2288101,and 82130010)the Innovation Program of Shanghai Municipal Education Commission(2021 Science and Technology Creation-03-1).
文摘Mitochondrial transplantation promotes cardiac repair following injury;however,its effects on limb ischemia due to peripheral artery disease(PAD)remain unclear.In this study,transplantation with mitochondria isolated from both murine muscle tissue and human arterial blood significantly promotes revascularization and blood flow recovery in a hindlimb ischemia mouse model.Our findings further show that transplanted mitochondria promote macrophages infiltrating into ischemic regions.Additionally,internalization of the mitochondria promotes macrophage M2-like polarization,resulting in increased pro-angiogenic factors expression and secretion and subsequent endothelial cell and smooth muscle cell proliferation.In conclusion,mitochondrial transplantation shows considerable potential in improving peripheral ischemia and provides therapeutic options for patients with PAD.
基金supported by National Natural Science Foundation of China grants 81900434(Dr.Bai Y.),82230009 and 82430016(Dr.Zou Y.),82170255(Dr.Wang S.),82200541(Dr.Guo F.)Program by Shanghai Municipality in 2021(21PJD013)+2 种基金Shanghai Natural Science grant(24ZR1409800)the Fudan University(IDF152064/016)by grants to JPC from the National Institutes of Health(R0-1 HL148338 and HL133254).
文摘EphrinB2(erythropoietin-producing hepatoma interactor B2)is a key Eph/ephrin family member,promoting angiogenesis,vasculogenesis,and lymphangiogenesis during embryonic development.However,the role of EphrinB2 in cardiac lymphangiogenesis following myocardial infarction(MI)and the potential molecular mechanism remains to be demonstrated.This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway.Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI.At the same time,overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart.The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in Lyve1 knockout mice.Mechanistically,EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation.EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3(FLT4)promoter,and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function.We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.
