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Endothelial cell mig ration, which is critical for new sprout formation during angiogenesis, requires continuous turnover of cellcell interactions and of cellmatrix interactions.Cellcell interactions between endothelial cells are maintained in part by catenin localized at cellcell junctions in cadherin complexes of capillary endothelial cells in vitro.Treatment of these cells with bFGF shifts catenin to the cytoplasm, which loosens cellcell adhesion and facilitates endothelial mig ration.However, cotreatment with endostatin transiently blocks this shift.Cellmatrix interactions are maintained in part by formation of focal adhesions and actin stressfibers.Either bFGF or endostatin alone, induced tyrosine phosphorylation of focal adhesion kinase and paxillin, which promoted formation of focal adhesions and actin stressfibers.However, when microvascular endothelial cells were cotreated with bFGF and endostatin, focal adhesion and actin stressfibers were decreased, which decreased mig ration of endothelial cells.In an in vivo situation, the entire vascular bed would be exposed to circulating endostatin.But its antiangiogenic effect would only become evident in areas of high growth factor stimulation, such as those present in the tumor endothelium.Taken together, these results provide a plausible mechanism to explain clinical trial data in which antiangiogenic effects of endostatin are observed in the absence of systemic toxicity.Another antiangiogenic mechanism of endostatin in addition to its antiproliferative and antimotility effect on angiogenic endothelial cells is the stabilization of newly formed endothelial tubes.By immunohistochemistry, administered endostatin localizes to endothelial cellcell junctions as well as to adhesion sites between endothelial cells and their basement membrane, thus anchoring endothelial cells to each other and to their basement membrane. Endostatin does not localize to quiescent vasculature.High concentrations of endostatin were detected by immunohistology in rat and human brain tumors in and around endothelial cells, in tumors cells, and in macrophages and leukocytes in the tumors vascular bed, but Glimepiride normal brain showed no endostatin reactivity.This unique localization of endostatin only in newly formed angiogenic microvessels, appears to reverse the loosening of endothelial cells to each other and to their basement membrane, which was necessary for them to form angiogenic sprouts in thefirst place.Similar stabilizing effects of endostatin were observed in tumors in vivo, where administered endostatin was more abundant in association with angiogenic vessels Glimepiride undergoing maturation, mainly at the tumor marginal zone where angiogenesis was highly active.Endostatin immunostaining is present during vascular formation up to the stage exhibiting one layer of periendothelial cells, but disappears in further stabilized vessels that have more than one layer of these cells in their wall.This suggests that the vascular stabilizing effect of endostatin occurs earlier than the integration of periendothelial cells into the vascular wall.A subsequent step of vascular stabilization by recruitment and integration of periendothelial cells is mediated by angiopoietin, TGF, and PDGF.This process converts the angiogenic blood vessels into the quiescent phenotype, thereby inhibiting tumor vascularization.One of the potential consequences of the angiogenic switch may be the reduction of vascular pemeability leading to tumor regression.Proangiogenic proteins such as bFGF increase the secretion of uPA and plasminogen activator inhibitor leading to an overall increase in proteolytic activity prerequisite for endothelial cell sprouting and tube formation.

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