Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies

Abstract

In addition to long term regulation of angiogenesis, angiogenic growth factor signaling through nitric oxide (NO) acutely controls blood flow and hemostasis. Inhibition of this pathway may account for the hypertensive and prothrombotic side effects of vascular endothelial growth factor antagonists currently used for cancer treatment. The first identified endogenous angiogenesis inhibitor, thrombospondin-1, also controls tissue perfusion, hemostasis, and radiosensitivity by antagonizing NO signaling. We examine the role of these and other emerging activities of thrombospondin-1 in cancer. Clarifying how endogenous and therapeutic angiogenesis inhibitors regulate vascular NO signaling could facilitate development of more selective inhibitors.The insight that tumor growth requires angiogenesis led to the development and clinical use of angiogenesis inhibitors as cancer therapeutics. The drugs bevacizumab, sorafenib, and sunitinib, which are approved by the US Food and Drug Administration for the treatment of several cancers, act specifically or in part by blocking the angiogenic activity of the vascular endothelial growth factor (VEGF) pathway. These targeted drugs significantly extend survival of cancer patients but have cardiovascular side effects that include hypertension [G] and thrombosis [G] [1][2][3] . Although most attempts to define the etiology of their hypertensive activity have focused on long term changes in vessel architecture, VEGF signaling via nitric oxide (NO) also has acute effects on vessel tone [G] 4,5 , and hypertension induced by the experimental VEGF receptor kinase inhibitor cediranib was recently shown to be caused by acute disruption of NO synthesis in vascular endothelium 6 . Recent studies of the first identified endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1), reveal that it also inhibits NO-mediated signaling to acutely control tissue perfusion [G] and hemostasis [G] 7,8 .Interestingly, the pioneering work of Folkman and colleagues showed that tumors can produce circulating angiogenesis inhibitors 9 , and circulating TSP1 levels are elevated in people and mice with certain cancers [10][11][12] . The benefit to the tumor of circulating angiogenesis inhibitors, which in some cases are produced by stromal rather than tumor cells, is unclear. We propose that elevated plasma TSP1 can enhance tumor perfusion through its hypertensive activity. This review synthesizes emerging evidence that hemostasis and tissue blood flow are acute targets of both endogenous and therapeutic angiogenesis inhibitors and explores ways that this insight can be used to improve anti-angiogenic therapy. Nitric oxidePhysiological activity of NO was first described by Davy in 1800 13 , but its production by mammalian tissues and role as a signaling molecule in vascular cells was not discovered until the 1980s 14 . The primary endogenous source of NO in endothelial cells is the endothelial isoform of nitric oxide synthase [G] (eNOS, also known as NOS3). eNOS is a highly regulated enzyme th...

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Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

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