Rationale: Shear stress (SS) has an established role in atherosclerotic plaque localization, but how it exerts its protective effect is not fully understood. Objective: To test the hypothesis that SS may downregulate angiotensin type 1 receptors (AT1,Rs). Angiotensin II has been shown to be proinflammatory and to promote atherosclerosis. Methods and Results: Using immunohistochemistry, we found a pronounced expression of AT1R in the inner, atheroprone regions of the aortic arch of C57BL/6 and endothelial NO synthase-deficient (eNOS-/-) mice but not eNOS-overexpressing mice. In human umbilical vein endothelial cells (HUVECs), laminar SS (15 dyn/cm2) induced a biphasic decrease in AT1R protein expression characterized by a first reduction at 1 hour (31 ±4% of static control, P<0.01), partial recovery at 3 hours (65±9%), and a second more prolonged decline at 6,12, and 24 hours (48±9%, 36±9%, 33±5%, respectively, P<0.05). One and 24 hours of SS significantly reduced fluorescent angiotensin binding compared to static HUVECs. Shear-induced downregulation of AT1R was abolished by treatment with protein kinase A and G inhibitors or A-nitro-L-arginine methyl ester (L-NAME). Fittingly, stimulating static HUVECs with an NO donor decreased AT1R protein levels. RT-PCR revealed a significant (P<0.05) decrease of AT1R mRNA in HUVECs exposed to SS during 3 (6±2% of static control), 6 (4±1%), 12 (4±1%), and 24 hours (15±4%), suggesting a transcriptional downregulation of AT1R at length. Finally, angiotensin-induced vascular cell adhesion molecule was abated in HUVECs exposed to SS and in the outer aortic arch of mice. Conclusions: Our results demonstrate that SS may convey some of its atheroprotective effects through downregulation of AT1R in endothelial cells.

Additional Metadata
Keywords Angiotensin, Atherosclerosis, Endothelium, Nitric oxide, Shear stress
Persistent URL dx.doi.org/10.1161/CIRCRESAHA.109.204040, hdl.handle.net/1765/25283
Citation
Ramkhelawon, B, Vilar, J, Rivas, D, Lehoux, S, Mees, B.M.E, Tedgui, A, & de Crom, M.P.G. (2009). Shear stress regulates angiotensin type 1 receptor expression in endothelial cells. Circulation Research, 105(9), 869–875. doi:10.1161/CIRCRESAHA.109.204040