Mirza M.K.,Center for Lung and Vascular Biology |
Sun Y.,Center for Lung and Vascular Biology |
Zhao Y.D.,Center for Lung and Vascular Biology |
Potula H.-H.S.K.,Center for Lung and Vascular Biology |
And 4 more authors.
Journal of Experimental Medicine | Year: 2010
Repair of the injured vascular intima requires a series of coordinated events that mediate both endothelial regeneration and reannealing of adherens junctions (AJs) to form a restrictive endothelial barrier. The forkhead transcription factor FoxM1 is essential for endothelial proliferation after vascular injury. However, little is known about mechanisms by which FoxM1 regulates endothelial barrier reannealing. Here, using a mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO) and primary cultures of ECs with small interfering RNA (siRNA)-mediated knockdown of FoxM1, we demonstrate a novel requisite role of FoxM1 in mediating endothelial AJ barrier repair through the transcriptional control of β-catenin. In the FoxM1 CKO lung vasculature, we observed persistent microvessel leakage characterized by impaired reannealing of endothelial AJs after endothelial injury. We also showed that FoxM1 directly regulated β-catenin transcription and that reexpression of β-catenin rescued the defective AJ barrier-reannealing phenotype of FoxM1-deficient ECs. Knockdown of β-catenin mimicked the phenotype of defective barrier recovery seen in FoxM1-deficient ECs. These data demonstrate that FoxM1 is required for reannealing of endothelial AJs in order to form a restrictive endothelial barrier through transcriptional control of β-catenin expression. Therefore, means of activating FoxM1-mediated endothelial repair represent a new therapeutic strategy for the treatment of inflammatory vascular diseases associated with persistent vascular barrier leakiness such as acute lung injury. © 2010 Mirza et al. Source
Zhang M.,University of Illinois at Chicago |
Zhang M.,Center for Lung and Vascular Biology |
Malik A.B.,University of Illinois at Chicago |
Malik A.B.,Center for Lung and Vascular Biology |
And 2 more authors.
Current Opinion in Hematology | Year: 2014
PURPOSE OF REVIEW: This review identifies recent advances in the field of vascular repair by regenerative endothelial cells and endothelial progenitor cells (EPCs). RECENT FINDINGS: A growing number of studies indicate that bone marrow-derived circulating EPCs do not engraft into blood vessels, but that such circulating cells may regulate vascular repair via paracrine mechanisms. Novel modes of paracrine regulation are being uncovered, such as the release of endothelial cell-derived microparticles or microvesicles that contain microRNAs which can promote vascular repair. Instead of circulating cells, tissue-resident endothelial cells or EPCs may primarily drive the restoration of vascular function after endothelial injury. In addition to the generation of endothelial cells/EPCs from pluripotent stem cells, direct reprogramming of fibroblasts to endothelial cells/EPCs is becoming an important source of regenerative vascular cells. SUMMARY: Ongoing efforts to understand the mechanisms that regulate vascular repair by resident regenerative vascular cells as well as their generation from fibroblasts and pluripotent stem cells will form the basis of future regenerative therapies. © 2014 Wolters Kluwer Health. Source
Tran K.A.,Illinois College |
Tran K.A.,Center for Lung and Vascular Biology |
Zhang X.,Illinois College |
Zhang X.,Center for Lung and Vascular Biology |
And 9 more authors.
Circulation | Year: 2016
Background - The blood-brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results - Using a mouse model with tamoxifen-inducible endothelial cell-restricted disruption of ctnnb1 (iCKO), we show here that endothelial β-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear β-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. Conclusions - These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation. © 2015 American Heart Association, Inc. Source
Oshikawa J.,Center for Lung and Vascular Biology |
Oshikawa J.,Center for Cardiovascular Research |
Kim S.-J.,Center for Lung and Vascular Biology |
Kim S.-J.,Center for Cardiovascular Research |
And 12 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2012
A longevity adaptor protein, is demonstrated as a key regulator of reactive oxygen species (ROS) metabolism involved in aging and cardiovascular diseases. Vascular endothelial growth factor (VEGF) stimulates endothe-lial cell (EC) migration and proliferation primarily through the VEGF receptor-2 (VEGFR2). We have shown that ROS derived from Rac1-dependent NADPH oxidase are involved in VEGFR2 autophosphor-ylation and angiogenic-related responses in ECs. However, a role of p66Shc in VEGF signaling and physiological responses in ECs is unknown. Here we show that VEGF promotes p66Shc phosphoryla-tion at Ser36 through the JNK/ERK or PKC pathway as well as Rac1 binding to a nonphosphorylated form of p66Shc in ECs. Depletion of endogenous p66Shc with short interfering RNA inhibits VEGF-induced Rac1 activity and ROS production. Fractionation of caveolin-enriched lipid raft demonstrates that p66Shc plays a critical role in VEGFR2 phosphorylation in caveolae/lipid rafts as well as downstream p38MAP kinase activation. This in turn stimulates VEGF-induced EC migration, proliferation, and capillary-like tube formation. These studies uncover a novel role of p66Shc as a positive regulator for ROS-dependent VEGFR2 signaling linked to angiogen-esis in ECs and suggest p66Shc as a potential therapeutic target for various angiogenesis-dependent diseases. © 2012 the American Physiological Society. Source
Ashino T.,University of Illinois at Chicago |
Sudhahar V.,University of Illinois at Chicago |
Urao N.,Center for Lung and Vascular Biology |
Oshikawa J.,Center for Lung and Vascular Biology |
And 12 more authors.
Circulation Research | Year: 2010
Rationale: Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. Objective: To determine the role of copper transporter ATP7A in PDGF-induced VSMC migration. Methods and results: Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addition, ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was observed by synchrotron-based X-ray fluorescence microscopy at neointimal VSMCs in wire injury model. Conclusions: These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis. © 2010 American Heart Association, Inc. Source