Microparticles harboring Sonic Hedgehog promote angiogenesis through the upregulation of adhesion proteins and proangiogenic factors
Microparticles harboring Sonic Hedgehog promote angiogenesis through the upregulation of adhesion proteins and proangiogenic factors
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DOI：
10.1093/carcin/bgp030
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发表时间：
2009-04-01
期刊：
影响因子：
4.7
通讯作者：
Martinez, Maria Carmen
中科院分区：
文献类型：
--
作者：
Soleti, Raffaella;Benameur, Tarek;Martinez, Maria Carmen
微颗粒（MPs）是细胞刺激或凋亡后从质膜产生的小碎片。我们最近的研究表明，含有形态因子Sonic Hedgehog （MPs(Shh+)）的MPs通过内皮细胞释放一氧化氮来纠正内皮细胞损伤[Agouni， Mostefai, Porro, Carusio, Favre, Richard, Henrion, Martinez and Andriantsitohaina（2007）中华医学杂志，21,2735-2741]。在这里，我们发现MPs（Shh+）在体外人内皮细胞模型中诱导毛细血管样结构的形成，尽管它们抑制细胞迁移。此外，MPs（Shh+）调节细胞增殖。MPs（Shh+）通过Rho相关的含卷曲卷曲的蛋白激酶抑制剂敏感途径，增加了细胞粘附和参与这一过程的蛋白的表达，如Rho A和局灶活化激酶的磷酸化。通过定量逆转录聚合酶链反应和western blot检测，我们发现MPs（Shh+）增加了促血管生成因子的信使RNA和蛋白质水平。尽管血管内皮生长因子表达，但内皮细胞的条件培养基处理avec MPs（Shh+）减少血管生成。有趣的是，当使用小干扰RNA沉默Shh受体或使用环巴胺抑制Sonic Hedgehog （Shh）信号传导时，MPs（Shh+）对毛细血管样结构形成、粘附分子表达和促血管生成因子的影响被逆转。综上所述，我们发现MPs携带的Shh （Shh+）可能通过直接和间接的机制调节血管生成，并且我们提出，在与肿瘤生长相关的病理中，MPs携带Shh可能有助于血管网络的产生。
Microparticles (MPs) are small fragments generated from the plasma membrane after cell stimulation or apoptosis. We have recently shown that MPs harboring the morphogen Sonic Hedgehog (MPs(Shh+)) correct endothelial injury by release of nitric oxide from endothelial cells [Agouni, Mostefai, Porro, Carusio, Favre, Richard, Henrion, Martinez and Andriantsitohaina (2007) FASEB J., 21, 2735-2741]. Here, we show that MPs(Shh+) induce the formation of capillary-like structures in an in vitro model using human endothelial cells, although they inhibited cell migration. Besides, MPs(Shh+) regulate cell proliferation. Both cell adhesion and expression of proteins involved in this process such as Rho A and phosphorylation of focal-activated kinase were increased by MPs(Shh+), via a Rho-associated coiled-coil-containing protein kinase inhibitor-sensitive pathway. We demonstrate that MPs(Shh+) increase messenger RNA and protein levels of proangiogenic factors as measured by quantitative reverse transcription-polymerase chain reaction and western blot. In spite of vascular endothelial growth factor expression, conditioned media from endothelial cells treated avec MPs(Shh+) reduces angiogenesis. Interestingly, the effects induced by MPs(Shh+) on the formation of capillary-like structures, expression of adhesion molecules and proangiogenic factors were reversed after silencing of the Shh receptor, using small interfering RNA or when Sonic Hedgehog (Shh) signaling was pharmacologically inhibited with cyclopamine. Taken together, we show that Shh carried by MPs(Shh+) regulate angiogenesis probably through both a direct and an indirect mechanisms, and we propose that MPs harboring Shh may contribute to the generation of a vascular network in pathologies associated with tumor growth.