Angiostatin Inhibition of Vascular Endothelial Growth Factor– Stimulated Nitric Oxide Production in Endothelial Cells

Abstract

Abstract. Angiostatin (AS), a proteolytic fragment of plasminogen, is a potent antiangiogenic factor. It was reported that AS attenuates the vasodilatory response to vascular endothelial growth factor (VEGF) in isolated interventricular arterioles. Here, we investigated the effect of AS on nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs). AS inhibited VEGF-stimulated NO production in a dose-dependent manner, whereas AS alone did not affect basal NO production. Disruption of kringle structures by reduction of disulfide bonds resulted in the loss of the inhibitory effect of AS on VEGF-stimulated NO production. To elucidate how AS might impair VEGF activation of endothelial NO synthase (eNOS), we further examined whether AS would affect Ca 2+ -dependent and -independent pathways of eNOS activation. AS had no effect on the transient increase in cytosolic Ca 2+ levels elicited by VEGF. In contrast, AS prevented VEGF-potentiated eNOS phosphorylation at Ser1177. These results clearly indicate that AS inhibits VEGF-stimulated NO production in HUVECs without affecting basal NO production. The kringle structures of AS are required for this effect, and impairment of Ser1177 phosphorylation of eNOS might be involved in the inhibition of VEGF-stimulated NO production by AS.

Cholesterol Effects on Endoglin and Its Downstream Pathways in ApoE/LDLR Double Knockout Mice

“…47 Moreover, VEGF stimulates production of NO. 48 In addition, VEGF expression is increased by ALK-1 in vitro. 33 In this study, we demonstrated that cholesterol administration reduces endoglin/ALK-1/ VEGF expression in the murine aorta and increases atherosclerotic plaque size, which suggests that cholesterol might affect NO production by affecting of this pathway and thus STRASKY Z et al…”

Renal Vascular Structure and Rarefaction

“…Angiostatin is a MMP-induced proteolytic cleavage product of plasminogen that is capable of inhibiting angiogenesis, promoting apoptosis of endothelial cells, and disrupting capillary integrity leading to capillary dropout (6). Angiostatin is a potent inhibitor of VEGF and downstream mediators (146,161), has been shown to be persistently elevated after ischemic renal injury, and can significantly reduce VEGF-induced proliferation and repair of peritubular capillaries, consequently accelerating tubular and interstitial damage (110). Another potent extracellular antiangiogenic factors and inhibitors of cell proliferation that are highly expressed in the kidney is endostatin.…”

Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis

“…However, although we have shown that such factors are also upregulated in the stenotic kidney (10,11,15), their increase is accompanied not only by marked fibrosis, but also a significant MV rarefaction. The accumulation of extracellular matrix in the fibrotic kidney not only represents a buildup of scar tissue, but also generates an active source of potential antiangiogenic mediators, such as angiostatin, a potent inhibitor of VEGF and downstream mediators (65,75). Angiostatin has been shown to be persistently elevated after ischemic renal injury and can significantly reduce VEGF-induced proliferation and repair of peritubular capillaries, hence accelerating tubular and interstitial damage (52).…”