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High concentrations of endostatin also interact with tropomyosin to interrupt microf ilament integrity, which inhibits endothelial motility and may par ticipate in partin endothelial apoptosis.Endostatin also binds to glypicans on the endothelial cell surface at concentrations which suggest that glypicans may be low aff inity endostatin receptors.Inhibition of cyclin D causing G arrest of endothelial cells.Endostatin causes G arrest in endothelial cells, by decreasing the hyperphosphorylated retinoblastoma gene product and downregulating cyclin D mRNA and protein.Transcription through the LEF site in the cyclin D promoter is essential for endostatins inhibitory activity.VEGF stimulates synthesis of endothelial nitric oxide. Nitric oxide synthesis also appears to be critical for the mitogenic effect of VEGF on endothelial cells.Inhibition of nitric oxide synthesis also blocks tumor angiogenesis.We have previously proposed another role for nitric oxide synthesis in angiogenesis: early vasodilation of preexisting quiescent vessels as a prerequisite for sprout formation.Hypoxic downregulation of endostatin production by endothelial cells and pericytes.These results imply that: decreased endostatin production by hypoxic pericytes andor endothelial cells may be another mechanism to facilitate the angiogenic switch in a tumor; pericytes may employ endostatin as one of the strategies to inhibit endothelial proliferation under normal conditions; and the treatment of a patient with a large tumor burden or with a tumor with a large hypoxic center, may require high doses of endostatin at the beginning of therapy, because of endostatin degradation.During development of the eye, hyaloid vessels supply the vitreous and the lens.Subsequently, these vessels reg ress leaving a transparent vitreous and lens.Endostatin is thought to play a key role in regression of the hyaloid vessels because they fail to regress in endostatins absence.The positive regulators include VEGFA,VEGFC, bFGF, HGF, angiopoietin, PDGF, heparanse and sphingosine phosphate, among others.The negative regulators include endostatin, platelet factor, thrombospondin, plasminogen, and antiplasmin, among others.These stimulators and inhibitors of endothelial cell migration and proliferation may be released into a blood clot in a wound in an orchestrated sequence to regulate neovascularization.For example, thrombin induces the release of the proangiogenic protein VEGF from platelets.Thrombin also induces the release of endostatin from platelets.Thrombin induction of endostatin release is mediated by proteinaseactivated receptor, a mechanism that is independent of platelet aggregation and of the action of ADP.When a clot forms in a wound, invasion by microvascular endothelial cells is initially inhibited, which avoids premature clot lysis.Subsequently, endothelial cells are recruited into the clot during its neovascularization. It is not known how the release of negative and positive regulators of endothelial migration from platelets is orchestrated in a wound.Recent evidence, however, reveals that if a thrombus in a large vessel is recanalized, the neovasculature is made up mainly of bone marrowderived endothelial cells.This is analgous to cer tain tumors that recruit the majority of their endothelial cells from bone marrow.Endostatin is also released from platelets by certain drugs, such as ticlopidine, which inhibits platelet agg regation by blocking the action of ADP with its receptor.The nonsteroidal antiinflammatory drugs celecoxib and flurbiprofen or HCT, all of which are cyclooxygenase inhibitors, also release endostatin from platelets and elevate the plasma level of endostatin.

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