Rap1 promotes endothelial mechanosensing complex formation,NO release and normal endothelial function |
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| Authors: | Sribalaji Lakshmikanthan Xiaodong Zheng Yoshinori Nishijima Magdalena Sobczak Aniko Szabo Jeannette Vasquez‐Vivar David X Zhang Magdalena Chrzanowska‐Wodnicka |
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| Institution: | 1. Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA;2. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA;3. Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA;4. Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA;5. Department of Biophysics and Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI, USA |
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| Abstract: | 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. |
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| Keywords: | mechanotransduction nitric oxide shear stress small GTPase Rap1 vasodilation |
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