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(Circulation Research. 2009;105:869.)
© 2009 American Heart Association, Inc.

Cellular Biology

Shear Stress Regulates Angiotensin Type 1 Receptor Expression in Endothelial Cells

Bhama Ramkhelawon, Jose Vilar, Daniel Rivas, Barend Mees, Rini de Crom, Alain Tedgui, Stéphanie Lehoux

From the Paris Cardiovascular Research Center (B.R., J.V., A.T., S.L.), Institut National de la Santé et de la Recherche Médicale U970, Hôpital Européen Georges Pompidou, France; Lady Davis Institute for Medical Research (D.R., S.L.), McGill University, Montreal, Canada; and Department of Vascular Surgery (B.M., R.d.C.) and Cell Biology & Genetics (B.M.), Erasmus University medical Center, Rotterdam, The Netherlands.

Correspondence to Dr Stéphanie Lehoux, Lady Davis Institute for Medical Research, McGill University, 3755 Cote Ste Catherine, Montreal, Quebec H3T 1E2, Canada. E-mail stephanie.lehoux{at}mcgill.ca

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 (AT₁Rs). 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 N^G-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.

Key Words: shear stress • angiotensin • nitric oxide • endothelium • atherosclerosis