Yuan Gongsheng, Yang Shu-Ting, Yang Shuying
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA19104, USA.
Center for Innovation & Precision Dentistry, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA19104, USA.
Cell Insight. 2022 Aug 17;1(5):100055. doi: 10.1016/j.cellin.2022.100055. eCollection 2022 Oct.
Angiogenesis is the formation of new capillaries that plays an essential role in the pathogenesis of inflammatory arthritis. However, the cellular and molecular mechanisms remain unclear. Here, we provide the first evidence that regulator of G-protein signaling 12 (RGS12) promotes angiogenesis in inflammatory arthritis through governing ciliogenesis and cilia elongation in endothelial cells. The knockout of RGS12 inhibits the development of inflammatory arthritis with the reduction in clinical score, paw swelling, and angiogenesis. Mechanistically, RGS12 overexpression (OE) in endothelial cells increases cilia number and length, and thereby promotes cell migration and tube-like structure formation. The knockout of cilia marker protein Intraflagellar transport (IFT) 80 blocked the increase in cilia number and length caused by RGS12 OE. Moreover, the results from LC/MS and IP analysis showed that RGS12 is associated with cilia-related protein MYC binding protein 2 (MYCBP2), which enhances the phosphorylation of MYCBP2 to promote ciliogenesis in endothelial cells. These findings demonstrate that upregulation of RGS12 by inflammation enhances angiogenesis by promoting cilia formation and elongation via activation of MYCBP2 signaling during inflammatory arthritis pathogenesis.
血管生成是新毛细血管的形成过程，在炎症性关节炎的发病机制中起着至关重要的作用。然而，其细胞和分子机制仍不清楚。在此，我们首次提供证据表明，G蛋白信号调节因子12（RGS12）通过调控内皮细胞的纤毛发生和纤毛伸长，促进炎症性关节炎中的血管生成。RGS12基因敲除抑制了炎症性关节炎的发展，临床评分、爪肿胀和血管生成均降低。机制上，内皮细胞中RGS12过表达（OE）增加了纤毛数量和长度，从而促进细胞迁移和管状结构形成。纤毛标记蛋白鞭毛内运输（IFT）80基因敲除阻断了RGS12过表达引起的纤毛数量和长度增加。此外，液相色谱/质谱（LC/MS）和免疫沉淀（IP）分析结果表明，RGS12与纤毛相关蛋白MYC结合蛋白2（MYCBP2）相关，可增强MYCBP2的磷酸化，从而促进内皮细胞的纤毛发生。这些发现表明，炎症导致的RGS12上调通过在炎症性关节炎发病机制中激活MYCBP2信号通路促进纤毛形成和伸长，从而增强血管生成。
