Shear Stress Regulates Angiotensin Type 1 Receptor Expression in Endothelial Cells

B Ramkhelawon, J Vilar, D Rivas, Barend Mees, Rini Crom, A Tedgui, S Lehoux

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Abstract

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 (AT(1)Rs). Angiotensin II has been shown to be proinflammatory and to promote atherosclerosis. Methods and Results: Using immunohistochemistry, we found a pronounced expression of AT(1)R 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/cm(2)) induced a biphasic decrease in AT(1)R 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 AT(1)R 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 AT(1)R protein levels. RT-PCR revealed a significant (P<0.05) decrease of AT(1)R 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 AT(1)R 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 AT(1)R in endothelial cells. (Circ Res. 2009; 105: 869-875.)
Original languageUndefined/Unknown
Pages (from-to)869-U77
JournalCirculation Research
Volume105
Issue number9
DOIs
Publication statusPublished - 2009

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