Identification of sokotrasterol sulfate as a novel proangiogenic steroid
Identification of sokotrasterol sulfate as a novel proangiogenic steroid
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DOI：
10.1161/01.res.0000233316.17882.33
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发表时间：
2006-08-04
影响因子：
20.1
通讯作者：
Karsan, Aly
中科院分区：
文献类型：
--
作者：
Murphy, Siun;Larrivee, Bruno;Karsan, Aly
利用外源性药物促进缺血组织新生血管形成的潜力已成为一个令人兴奋的治疗领域。在试图确定新的小分子血管生成促进活性，我们筛选了天然产物库，并确定了硫酸化类固醇，sokotrasterol硫酸盐，诱导血管生成在体外和体内。我们发现，sokotrasterol硫酸盐促进内皮发芽在体外，新血管形成的鸡绒毛尿囊膜，并加速血管生成和再灌注在小鼠后肢缺血模型。我们证明了类固醇的硫酸化对于促进血管生成是至关重要的，因为硫酸化类固醇没有表现出内皮发芽活性。因此，我们开发了一种化学合成的sokotrasterol硫酸盐类似物，2 β，3 α，6 α-胆甾烷三硫酸盐，其在后肢缺血模型中表现出等效活性，并导致产生稳定的血管，其在停止治疗后持续存在。硫酸sokotrasterol的功能依赖于环氧合酶-2活性和血管内皮生长因子诱导，因为环氧合酶-2或血管内皮生长因子的抑制阻断了血管生成。α（v）β（3）整联蛋白的表面表达也是功能所必需的，因为α（v）β（3）整联蛋白的中和而不是β（1）整联蛋白的中和，结合消除了响应于硫酸索曲甾醇的内皮发芽和抗凋亡活性。我们的研究结果表明，sokotrasterol硫酸盐及其类似物可以促进血管生成在体外和体内，并可能用于促进新生血管形成，以减轻血管闭塞性疾病的后遗症。
The potential to promote neovascularization in ischemic tissues using exogenous agents has become an exciting area of therapeutics. In an attempt to identify novel small molecules with angiogenesis promoting activity, we screened a library of natural products and identified a sulfated steroid, sokotrasterol sulfate, that induces angiogenesis in vitro and in vivo. We show that sokotrasterol sulfate promotes endothelial sprouting in vitro, new blood vessel formation on the chick chorioallantoic membrane, and accelerates angiogenesis and reperfusion in a mouse hindlimb ischemia model. We demonstrate that sulfation of the steroid is critical for promoting angiogenesis, as the desulfated steroid exhibited no endothelial sprouting activity. We thus developed a chemically synthesized sokotrasterol sulfate analog, 2 beta,3 alpha,6 alpha-cholestanetrisulfate, that demonstrated equivalent activity in the hindlimb ischemia model and resulted in the generation of stable vessels that persisted following cessation of therapy. The function of sokotrasterol sulfate was dependent on cyclooxygenase-2 activity and vascular endothelial growth factor induction, as inhibition of either cyclooxygenase-2 or vascular endothelial growth factor blocked angiogenesis. Surface expression of alpha(v)beta(3) integrin was also necessary for function, as neutralization of alpha(v)beta(3) integrin, but not beta(1) integrin, binding abrogated endothelial sprouting and antiapoptotic activity in response to sokotrasterol sulfate. Our findings indicate that sokotrasterol sulfate and its analogs can promote angiogenesis in vitro and in vivo and could potentially be used for promoting neovascularization to relieve the sequelae of vasoocclusive diseases.