Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner
Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner
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DOI：
10.1073/pnas.0502977102
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发表时间：
2005-09-13
影响因子：
11.1
通讯作者：
Roberts, DD
中科院分区：
文献类型：
--
作者：
Isenberg, JS;Ridnour, LA;Roberts, DD
氧化还原信号在血管内皮生长因子对血管生成的正调控中起着重要作用，但其在血管生成抑制剂信号转导中的作用尚不清楚。在三维培养中使用肌肉外植体，我们发现缺乏血管生成抑制剂血小板反应蛋白-1（TSP 1）的小鼠的外植体对外源性NO供体表现出过度的血管生成反应，这可以通过提供外源性TSP 1来逆转。为了确定由TSP 1抑制的基础，我们研究了TSP 1对内皮细胞对NO的几种促血管生成反应的影响。NO对内皮细胞增殖具有双相作用。在低剂量的NO的积极作用是敏感的cGMP信号和TSP 1的皮摩尔浓度的抑制。NO以cGMP依赖性方式刺激内皮细胞的定向（趋化性）和随机（化学动力学）运动。TSP 1有效地抑制由NO刺激的趋化性。低剂量的NO也以cGMP依赖的方式刺激内皮细胞在I型胶原上的粘附。TSP 1在cGMP的上游和下游都有效地抑制这种反应。NO刺激的内皮细胞反应被TSP 1的重组1型重复序列和CD 36激动剂抗体抑制，但不被TSP 1的N-末端部分抑制，表明CD 36或相关受体介导这些作用。这些结果表明，TSP 1和NO下游的促血管生成信号之间的有效拮抗作用。进一步阐明这种抑制性信号传导途径可能会确定新的分子靶点来调节病理性血管生成。
Redox signaling plays an important role in the positive regulation of angiogenesis by vascular endothelial growth factor, but its role in signal transduction by angiogenesis inhibitors is less clear. Using muscle explants in 3D culture, we found that explants from mice lacking the angiogenesis inhibitor thrombospondin-1 (TSP1) exhibit exaggerated angiogenic responses to an exogenous NO donor, which could be reversed by providing exogenous TSP1. To define the basis for inhibition by TSP1, we examined the effects of TSP1 on several proangiogenic responses of endothelial cells to NO. NO has a biphasic effect on endothelial cell proliferation. The positive effect at low doses of NO is sensitive to inhibition of cGMP signaling and picomolar concentrations of TSP1. NO stimulates both directed (chemotactic) and random (chemokinetic) motility of endothelial cells in a cGMP-dependent manner. TSP1 potently inhibits chemotaxis stimulated by NO. Low doses of NO also stimulate adhesion of endothelial cells on type I collagen in a cGMP-dependent manner. TSP1 potently inhibits this response both upstream and downstream of cGMP. NO-stimulated endothelial cell responses are inhibited by recombinant type 1 repeats of TSP1 and a CD36 agonist antibody but not by the N-terminal portion of TSP1, suggesting that CD36 or a related receptor mediates these effects. These results demonstrate a potent antagonism between TSP1 and proangiogenic signaling downstream of NO. Further elucidation of this inhibitory signaling pathway may identify new molecular targets to regulate pathological angiogenesis.