Angiostatin could have important effects on a variety of tissue targets, its benefit not being exclusively limited to the tumor microvasculature. Advanced atherosclerosis and neointimal hyperplasia are associated with extensive neovascularization. Angiostatin inhibits atherosclerosis development in apolipoprotein E null mice and reduces neointimal hyperplasia in response to balloon injury in rabbits. Adipose tissue is highly vascularized and exhibits angiogenic properties. Weight reduction in response to angiogenesis inhibitors is accompanied by evidence of adipose endothelial cell apoptosis, suggesting an antiangio-genic mechanism of action. Angiostatin is effective in reducing weight gain in obese (ob/ob) mice.
Angiostatin could be generated in virtually any tissue with the appropriate environmental conditions: ischemia, high oxidative stress, reduced NO production, and elevated MMP-2, -7, and -9 activity. Angiostatin has been demonstrated in tear fluid, where it has been proposed to protect against corneal neovascularization. In a canine model of repetitive coronary ischemia, treatment with L-NAME was associated with the accumulation of angiostatin in the myocardial interstitial fluid. It was postulated that angio-statin production may limit the development of coronary artery collaterals in response to ischemia.
An endothelium with intact angiogenesis capability may be important in the health of many tissues. Therefore angiostatin's actions on the microvasculature, especially its effects on the endothelium, could produce effects that extend well beyond an exclusive role in inhibiting angiogen-esis. An example is the reported ability of angiostatin to impair endothelium-dependent vasodilation. By reducing the interaction between eNOS and hsp90, angiostatin enhances O2t production, while decreasing NO production. This effect could regulate vasomotor tone and also have antiangiogenic effects, since many angiogenic growth factors including VEGF and FGF induce NO production. Furthermore, increased NO production with vasodilation is an early step in capillary beds undergoing angiogenesis. It is also possible that angiostatin could also inhibit vasodilation by blocking a^. Mogford et al.  have demonstrated that RGD pep-tides applied to rat arterioles produced concentration-dependent, sustained endothelium-independent vasodilation. Vasodilatory RGD-containing peptides can be produced endogenously during collagenolysis. These fragments may be produced during arterial remodeling and may contribute to maintaining luminal expansion.
The production of angiostatin during tissue hypoxia could exacerbate the development of pulmonary hypertension. The expression of angiogenic growth factors may be one protective mechanism to reduce the severity of pulmonary arterial hypertension (PAH). When angiostatin is overexpressed in the lung of chronically hypoxic mice, they developed more severe pulmonary artery hypertension, right ventricular hypertrophy, and muscularization of pulmonary artery vessels . It is possible that a strategy aimed at inhibiting endogenous angiostatin production could slow the progression of PAH.
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