title: Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function.
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.
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors: Sribalaji
authors: S
authors: Lakshmikanthan
authors: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Xiaodong
authors: X
authors: Zheng
authors: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Yoshinori
authors: Y
authors: Nishijima
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors: Magdalena
authors: M
authors: Sobczak
authors: Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Aniko
authors: A
authors: Szabo
authors: Department of Biophysics and Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Jeannette
authors: J
authors: Vasquez-Vivar
authors: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: David X
authors: DX
authors: Zhang
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA magdalena.chrzanowska@bcw.edu.
authors: Magdalena
authors: M
authors: Chrzanowska-Wodnicka
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002199:Capillary Permeability / Q000235:genetics; D004727:Endothelium / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D015398:Signal Transduction; D014664:Vasodilation / Q000235:genetics; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D020827:rap1 GTP-Binding Proteins
keywords: mechanotransduction; nitric oxide; shear stress; small GTPase Rap1; vasodilation