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Background— Essential hypertension involves an increase in sympathetic nervous system activity and an associated decrease in β-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 ≈2-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 Gi -signaling inhibition or chronic β1 AR inhibition after 7 days of CGP20712A, whereas the β2 AR antagonist ICI 118,551 was ineffective. α1 AR response was not altered, nor was βAR-mediated dilation in male blood vessels, whereas norepinephrine sensitivity was increased. In contrast, female VSM-GRK5 blood vessels have diminished βAR-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 Gi and, at least in part, by β1 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.

circulation

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

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

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