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

Sribalaji Lakshmikanthan, Bartosz J. Zieba, Zhi Dong Ge, Ko Momotani, Xiaodong Zheng, Hayley Lund, Mykhaylo V. Artamonov, Jason E. Maas, Aniko Szabo, David X. Zhang, John A. Auchampach, David L. Mattson, Avril V. Somlyo, Magdalena Chrzanowska-Wodnicka

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

OBJECTIVE - 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. APPROACH AND RESULTS - 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. CONCLUSIONS - 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.

Original languageEnglish (US)
Pages (from-to)1486-1494
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number7
DOIs
StatePublished - Jul 2014
Externally publishedYes

Keywords

  • relaxation
  • signal transduction
  • vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Lakshmikanthan, S., Zieba, B. J., Ge, Z. D., Momotani, K., Zheng, X., Lund, H., Artamonov, M. V., Maas, J. E., Szabo, A., Zhang, D. X., Auchampach, J. A., Mattson, D. L., Somlyo, A. V., & Chrzanowska-Wodnicka, M. (2014). Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure. Arteriosclerosis, thrombosis, and vascular biology, 34(7), 1486-1494. https://doi.org/10.1161/ATVBAHA.114.303678