Objective
Small GTPase 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 knockout (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 I receptor 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 (SM)-mediated vessel contraction and endothelium-dependent vessel dilation, two major mechanisms controlling basal vascular tone, were the basis for the hypertension. We found increased contractility upon stimulation with a thromboxane analogue 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. cAMP-dependent-relaxation in response to Rap1 activator, Epac, was decreased in vessels from Rap1b−/− mice. Defective endothelial release of dilatory nitric oxide (NO) in response to elevated blood flow leads to hypertension. We found that NO-dependent vasodilation was significantly inhibited in Rap1b-deficient vessels.
Conclusion
This is the first report to indicate that Rap1b in both SM and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone.