title: Shear stress regulates angiotensin type 1 receptor expression in endothelial cells.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Paris Cardiovascular Research Center, Institut National de la Santé et de la Recherche Médicale U970, Hôpital Européen Georges Pompidou, France.
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Jose
authors.initials: J
authors.lastname: Vilar
authors.forename: Daniel
authors.initials: D
authors.lastname: Rivas
authors.forename: Barend
authors.initials: B
authors.lastname: Mees
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lehoux
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011673:Pulsatile Flow; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow; D015398:Signal Transduction; D013314:Stress, Mechanical; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D020030:Nitric Oxide Donors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases