Vascular Smooth Muscle Overexpression of G Protein–Coupled Receptor Kinase 5 Elevates Blood Pressure, Which Segregates With Sex and Is Dependent on G _i -Mediated Signaling

Abstract

Background-Essential hypertension involves an increase in sympathetic nervous system activity and an associated decrease in ␤-adrenergic receptor (AR)-mediated dilation. In addition, increased levels of G protein-coupled receptor (GPCR) kinases (GRKs), which regulate GPCR signaling, are associated with increased blood pressure (BP). Methods and Results-We generated transgenic mice with Ϸ2-fold vascular smooth muscle (VSM)-specific overexpression of GRK5 to recapitulate a selective aspect of hypertension and understand the impact on GPCR regulation of BP. VSM-GRK5 mice were hypertensive, with a 25% to 35% increase in BP, whereas there was no concomitant cardiac or VSM hypertrophy. BP elevations were segregated with sex, with male mice having higher levels than female mice, and ovariectomy did not alter this phenotype. BP was restored to control values with pertussis toxin G i -signaling inhibition or chronic ␤ 1 AR inhibition after 7 days of CGP20712A, whereas the ␤ 2 AR antagonist ICI 118,551 was ineffective. ␣ 1 AR response was not altered, nor was ␤AR-mediated dilation in male blood vessels, whereas norepinephrine sensitivity was increased. In contrast, female VSM-GRK5 blood vessels have diminished ␤AR-mediated dilation and enhanced sensitivity to angiotensin II (Ang II). Conclusions-Our data suggest that in both male and female mice, VSM-specific overexpression of GRK5 elevates BP mediated by G i and, at least in part, by ␤ 1 AR in males and Ang II receptors in females. Understanding mechanisms underlying an increase in VSM-GRK5 may have a profound influence on the use and development of antihypertensive therapeutics.

Genetics of arterial hypertension and hypotension

“…Targeted overexpression of GRK2 to the vasculature is accompanied by increases in resting blood pressure and attenuated β-adrenergic signalling (Eckhart et al 2002). Similar results were obtained for the GRK5 isoform (Keys et al 2005). In addition to receptor desensitization, there is evidence that GRK2 is involved in the regulation of endothelial NO synthase (eNOS) activity, at least in hepatic portal endothelial cells (Fig.…”

Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of β-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor κB (NFκB) Activation

“…5A) (25) under the control of the SMC-specific SM22␣ promoter (28,40,41). Immunoblots of aortic extracts demonstrated that the total level of USP20 in the USP20-Tg was 2 Ϯ 1-fold more than endogenous USP20 levels in non-Tg and that DN-USP20-Tg expression was about 3 Ϯ 1-fold greater than endogenous USP20 levels (Fig.…”

G Protein–Coupled Receptor Kinase 4

“…The hypertension in male GRK5 transgenic mice is, in part, because of decreased ␤ 1 -adrenergic receptor activity, whereas the high blood pressure in female mice is because of increased activity of AT 1 Rs. 14 Dopamine D 2 R hypersensitivity occurs with disruption of the GRK6 gene in mice. 15 Therefore, abnormalities of GRK6 gene can lead to D 2 R supersensitivity, which can result in a decrease in norepinephrine release, leading to decreased blood pressure or, alternatively, causing an increase in D 2 R-mediated sodium transport in renal proximal tubules, leading to an increased blood pressure, instead.…”