文章：

血小板反应蛋白1对一氧化氮信号的调节：对抗血管生成治疗的影响

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

原文发布日期：2009-02-05

DOI: 10.1038/nrc2561

类型: Review Article

开放获取: 否

要点：

1. Nitric oxide (NO) mediates pro-angiogenic activities of vascular endothelial growth factor A (VEGFA) and a number of additional angiogenic factors that support the neovascularization of tumours. This signalling involves activation of soluble guanylate cyclase and downstream targets of cyclic GMP.
2. Thrombospondin 1 (TSP1) and TSP2 are endogenous angiogenesis inhibitors. Their expression is frequently lost during cancer progression, and overexpression suppresses tumour growth. TSP1 is a potent antagonist of NO signalling in vascular endothelial cells, vascular smooth muscle cells and platelets. TSP2 is substantially less active.
3. Antagonism of NO signalling can be mediated by TSP1 binding to two of its receptors, CD36 and CD47. CD47 mediates inhibition at much lower concentrations of TSP1, and CD47 is also required for signalling through CD36.
4. TSP1 signalling through CD47 redundantly inhibits NO signalling at the level of soluble guanylate cyclase and cGMP-dependent protein kinase.
5. In addition to long-term inhibition of angiogenesis, antagonism of NO signalling by TSP1 results in acute inhibition of tissue perfusion and acceleration of platelet haemostasis. Consequently, TSP1 and CD47 limit recovery of blood flow and tissue survival following ischaemic injuries. By contrast, tumour vasculature is resistant to acute vasodilation by NO, and increased circulating TSP1 produced by tumour stroma may instead indirectly increase tumour perfusion by limiting blood flow elsewhere.
6. These activities of TSP1 parallel the hypertensive and pro-thrombotic activities that are emerging as frequent side effects of therapeutic angiogenesis inhibitors, and both can be explained by inhibition of NO signalling.
7. TSP1 signalling through CD47 also limits soft tissue survival after radiation injury. Disruption of this pathway is a possible strategy to permit delivery of higher therapeutic radiation doses to tumours while selectively protecting surrounding healthy tissues.

要点翻译：

1. 一氧化氮（NO）介导血管内皮生长因子A（VEGFA）及多种其他促血管生成因子的活性，这些因子共同支持肿瘤的新血管生成。该信号通路涉及可溶性鸟苷酸环化酶的激活以及环磷酸鸟苷下游靶标的作用。
2. 血小板反应蛋白1（TSP1）与TSP2是内源性血管生成抑制剂。在癌症进展过程中，它们的表达常常缺失，而过表达则可抑制肿瘤生长。TSP1在血管内皮细胞、血管平滑肌细胞和血小板中是NO信号通路的高效拮抗剂，而TSP2的活性则显著较弱。
3. TSP1通过与其两个受体CD36和CD47结合来介导对NO信号通路的拮抗作用。CD47在极低浓度的TSP1下即可介导抑制效应，且CD47也是CD36信号传导所必需的。
4. TSP1通过CD47发出的信号，在可溶性鸟苷酸环化酶和cGMP依赖性蛋白激酶水平上冗余地抑制NO信号通路。
5. 除了长期抑制血管生成外，TSP1对NO信号通路的拮抗还会导致组织灌注的急性抑制和血小板止血的加速。因此，TSP1和CD47会限制缺血性损伤后血流的恢复和组织存活。相比之下，肿瘤血管系统对NO介导的急性血管舒张具有抵抗性，而肿瘤基质产生的循环TSP1增加可能通过限制其他部位的血流，间接提高肿瘤灌注。
6. TSP1的这些作用与治疗性血管生成抑制剂常见的副作用——高血压和促血栓形成活性相平行，且两者均可通过抑制NO信号通路来解释。
7. TSP1通过CD47发出的信号还会限制辐射损伤后软组织的存活。破坏这一通路可能作为一种策略，允许向肿瘤输送更高的治疗性辐射剂量，同时选择性保护周围健康组织。

英文摘要：

In addition to long-term regulation of angiogenesis, angiogenic growth factor signalling through nitric oxide (NO) acutely controls blood flow and haemostasis. Inhibition of this pathway may account for the hypertensive and pro-thrombotic side effects of the vascular endothelial growth factor antagonists that are currently used for cancer treatment. The first identified endogenous angiogenesis inhibitor, thrombospondin 1, also controls tissue perfusion, haemostasis and radiosensitivity by antagonizing NO signalling. 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 signalling could facilitate development of more selective inhibitors.

摘要翻译： 

除长期调控血管生成外，血管生成生长因子通过一氧化氮（NO）信号通路还可急性控制血流和止血。对该通路的抑制可能解释目前用于癌症治疗的血管内皮生长因子拮抗剂所引发的高血压和促血栓副作用。首个被发现的内源性血管生成抑制剂——血小板反应蛋白1，也通过拮抗NO信号调控组织灌注、止血及放射敏感性。我们探讨血小板反应蛋白1这些及其他新发现的功能在癌症中的作用。阐明内源性和治疗性血管生成抑制剂如何调控血管NO信号，将有助于开发更具选择性的抑制剂。

原文链接：

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