title: Angiotensinergic stimulation of vascular endothelium in mice causes hypotension, bradycardia, and attenuated angiotensin response.
abstract: It is not clear whether endothelial cell (EC) activation by the hormone angiotensin II (Ang II) modulates contraction of vascular smooth muscle cells (VSMCs) in the vasculature and whether impairment of this regulation in vivo contributes to hypertension. Delineation of the actions of Ang II through the type 1 receptor (AT1R) on ECs in the blood vessels has been a challenging problem because of the predominance of the AT1R functions in VSMCs that lie underneath the endothelium. We have obviated this limitation by generating transgenic (TG) mice engineered to target expression of the constitutively active N111G mutant AT1R only in ECs. In these TG mice, the enhanced angiotensinergic signal in ECs without infusion of Ang II resulted in hypotension and bradycardia. The pressor response to acute infusion of Ang II was significantly reduced. Increased expression of endothelial nitric oxide synthase and production of hypotensive mediators, nitric oxide and cyclic guanosine monophosphate, cause these phenotypes. Hypotension and bradycardia observed in the TG mice could be rescued by treatment with an AT1R-selective antagonist. Our results imply that the Ang II action by means of EC-AT1R is antagonistic to vasoconstriction in general, and it may moderate the magnitude of functional response to Ang II in VSMCs. This control mechanism in vivo most likely is a determinant of altered hemodynamic regulation involved in endothelial dysfunction in hypertensive cardiovascular disease.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Ramchandran
authors.forename: Takanobu
authors.initials: T
authors.lastname: Takezako
authors.forename: Yasser
authors.initials: Y
authors.lastname: Saad
authors.forename: Linda
authors.initials: L
authors.lastname: Stull
authors.forename: Bruno
authors.initials: B
authors.lastname: Fink
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Yamada
authors.forename: Sergey
authors.initials: S
authors.lastname: Dikalov
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Christine
authors.initials: C
authors.lastname: Moravec
authors.forename: Sadashiva S
authors.initials: SS
authors.lastname: Karnik
mesh_terms: D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression; D007022:Hypotension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000809:Angiotensins; D044140:Receptor, Angiotensin, Type 1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D042810:Receptor, TIE-1