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Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure.


ABSTRACT: Small GTPase Ras-related protein 1 (Rap1b) controls several basic cellular phenomena, and its deletion in mice leads to several cardiovascular defects, including impaired adhesion of blood cells and defective angiogenesis. We found that Rap1b(-/-) mice develop cardiac hypertrophy and hypertension. Therefore, we examined the function of Rap1b in regulation of blood pressure.Rap1b(-/-) mice developed cardiac hypertrophy and elevated blood pressure, but maintained a normal heart rate. Correcting elevated blood pressure with losartan, an angiotensin II type 1 receptor antagonist, alleviated cardiac hypertrophy in Rap1b(-/-) mice, suggesting a possibility that cardiac hypertrophy develops secondary to hypertension. The indices of renal function and plasma renin activity were normal in Rap1b(-/-) mice. Ex vivo, we examined whether the effect of Rap1b deletion on smooth muscle-mediated vessel contraction and endothelium-dependent vessel dilation, 2 major mechanisms controlling basal vascular tone, was the basis for the hypertension. We found increased contractility on stimulation with a thromboxane analog or angiotensin II or phenylephrine along with increased inhibitory phosphorylation of myosin phosphatase under basal conditions consistent with elevated basal tone and the observed hypertension. Cyclic adenosine monophosphate-dependent relaxation in response to Rap1 activator, Epac, was decreased in vessels from Rap1b(-/-) mice. Defective endothelial release of dilatory nitric oxide in response to elevated blood flow leads to hypertension. We found that nitric oxide-dependent vasodilation was significantly inhibited in Rap1b-deficient vessels.This is the first report to indicate that Rap1b in both smooth muscle and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone.

SUBMITTER: Lakshmikanthan S 

PROVIDER: S-EPMC4224284 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure.

Lakshmikanthan Sribalaji S   Zieba Bartosz J BJ   Ge Zhi-Dong ZD   Momotani Ko K   Zheng Xiaodong X   Lund Hayley H   Artamonov Mykhaylo V MV   Maas Jason E JE   Szabo Aniko A   Zhang David X DX   Auchampach John A JA   Mattson David L DL   Somlyo Avril V AV   Chrzanowska-Wodnicka Magdalena M  

Arteriosclerosis, thrombosis, and vascular biology 20140501 7


<h4>Objective</h4>Small GTPase Ras-related protein 1 (Rap1b) controls several basic cellular phenomena, and its deletion in mice leads to several cardiovascular defects, including impaired adhesion of blood cells and defective angiogenesis. We found that Rap1b(-/-) mice develop cardiac hypertrophy and hypertension. Therefore, we examined the function of Rap1b in regulation of blood pressure.<h4>Approach and results</h4>Rap1b(-/-) mice developed cardiac hypertrophy and elevated blood pressure, bu  ...[more]

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