Matsumoto Taro, Schiller Petter, Dieterich Lothar C, Bahram Fuad, Iribe Yuji, Hellman Ulf, Wikner Charlotte, Chan Gordon, Claesson-Welsh Lena, Dimberg Anna
Department of Genetics and Pathology, Rudbeck Laboratory, S-751 85 Uppsala, Sweden.
Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2123-30. doi: 10.1161/ATVBAHA.108.169128. Epub 2008 Sep 4.
Angiogenesis is an integral part of many physiological processes but may also aggravate pathological conditions such as cancer. Development of effective angiogenesis inhibitors requires a thorough understanding of the molecular mechanisms regulating vessel formation. The aim of this project was to identify proteins that regulate tubular morphogenesis of endothelial cells.
Phosphotyrosine-dependent affinity-purification and mass spectrometry showed tyrosine phosphorylation of ninein during tubular morphogenesis of endothelial cells. Ninein was recently identified as a centrosomal microtubule-anchoring protein. Our results show that ninein is localized in the cytoplasm in endothelial cells, and that it is highly expressed in the vasculature in normal and pathological human tissues. Using embryoid bodies as a model of vascular development, we found that ninein is abundantly expressed in the cytoplasm of endothelial cells during sprouting angiogenesis, in particular in the sprouting tip-cell. In accordance, siRNA-dependent silencing of ninein in endothelial cells inhibited tubular morphogenesis.
In this study, we show that ninein is expressed in developing vessels and in endothelial tip cells, and that ninein is critical for formation of the vascular tube. These data strongly implicate ninein as an important new regulator of angiogenesis.
血管生成是许多生理过程不可或缺的一部分，但也可能加剧诸如癌症等病理状况。开发有效的血管生成抑制剂需要深入了解调节血管形成的分子机制。本项目的目的是鉴定调节内皮细胞管状形态发生的蛋白质。
磷酸酪氨酸依赖性亲和纯化和质谱分析显示，在内皮细胞管状形态发生过程中九蛋白存在酪氨酸磷酸化。九蛋白最近被鉴定为一种中心体微管锚定蛋白。我们的结果表明，九蛋白在内皮细胞的细胞质中定位，并且在正常和病理人类组织的脉管系统中高度表达。利用胚状体作为血管发育模型，我们发现在发芽血管生成过程中，九蛋白在内皮细胞的细胞质中大量表达，尤其是在发芽尖端细胞中。相应地，在内皮细胞中通过RNA干扰依赖性沉默九蛋白可抑制管状形态发生。
在本研究中，我们表明九蛋白在发育中的血管和内皮尖端细胞中表达，并且九蛋白对血管管的形成至关重要。这些数据强烈表明九蛋白是血管生成的一个重要新调节因子。
