Rap1b in Smooth Muscle and Endothelium Is Required for Maintenance of Vascular Tone and Normal Blood Pressure

Abstract

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.

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

“…55,56 Consistent with this finding, 8-CPT-induced relaxation is decreased in mouse vessels lacking a direct target of EPAC, Rap1B. 57 Of particular importance, Rap1B knockout mice develop hypertension, in part, via functional changes to VSMC and this indicates an essential role of Rap1 and possibly EPAC in maintaining normal vascular physiology. 57 Various mechanisms that do not necessarily exclude the participation of PKA are involved in EPAC vasorelaxant effect.…”

“…57 Of particular importance, Rap1B knockout mice develop hypertension, in part, via functional changes to VSMC and this indicates an essential role of Rap1 and possibly EPAC in maintaining normal vascular physiology. 57 Various mechanisms that do not necessarily exclude the participation of PKA are involved in EPAC vasorelaxant effect. 56,58,59 EPAC mediates vasorelaxation by indirectly regulating the activity of Ca 2+ -sensitive and ATP-sensitive K + channels within the endothelium and on VSMCs ( Figure 5).…”

Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats

“…25 It is also reported that, in SHR, the resistant arteries have a weaker response to vasorelaxant substances than in WKY. 26 So we investigated the vascular relaxation of mesenteric arteries after CDCA delivery.…”

AT1 receptor signaling pathways in the cardiovascular system

“…AngII-dependent hypertension, but not vascular remodeling, is attenuated in c-Src+/− mice (31). Similarly, Ras-related protein 1 (Rap1b) knockdown or PDZ-RhoGEF/RhoA/Rho kinase signaling cascade promotes vascular contraction induced by AngII through inhibition of MLCP (32, 33). The AT1 receptor has also been shown to regulate vasoconstriction through phosphorylation of with-no-lysine (WNK) and Ste20/SPS1-related proline/alanine-rich kinase (SPAK) and subsequent modulation of Na-K-Cl cotransporter isoform 1 (NKCC1) (34).…”