Lakshmikanthan Sribalaji, Zheng Xiaodong, Nishijima Yoshinori, Sobczak Magdalena, Szabo Aniko, Vasquez-Vivar Jeannette, Zhang David X, Chrzanowska-Wodnicka Magdalena
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
EMBO Rep. 2015 May;16(5):628-37. doi: 10.15252/embr.201439846. Epub 2015 Mar 25.
Decreased nitric oxide (NO) bioavailability underlies a number of cardiovascular pathologies, including hypertension. The shear stress exerted by flowing blood is the main determinant of NO release. Rap1 promotes integrin- and cadherin-mediated signaling. Here, we show that Rap1 is a critical regulator of NO production and endothelial function. Rap1 deficiency in murine endothelium attenuates NO production and diminishes NO-dependent vasodilation, leading to endothelial dysfunction and hypertension, without deleterious effects on vessel integrity. Mechanistically, Rap1 is activated by shear stress, promotes the formation of the endothelial mechanosensing complex-comprised of PECAM-1, VE-cadherin and VEGFR2- and downstream signaling to NO production. Our study establishes a novel paradigm for Rap1 as a regulator of mechanotransduction.
一氧化氮（NO）生物利用度降低是包括高血压在内的多种心血管疾病的基础。流动血液施加的剪切应力是NO释放的主要决定因素。Rap1促进整合素和钙黏蛋白介导的信号传导。在此，我们表明Rap1是NO产生和内皮功能的关键调节因子。小鼠内皮细胞中Rap1的缺乏会减弱NO的产生并减少NO依赖性血管舒张，导致内皮功能障碍和高血压，而对血管完整性没有有害影响。从机制上讲，Rap1被剪切应力激活，促进由PECAM-1、VE-钙黏蛋白和VEGFR2组成的内皮机械传感复合物的形成以及下游向NO产生的信号传导。我们的研究建立了一种将Rap1作为机械转导调节因子的新范式。
