Published Online
on August 15, 2005

A more recent version of this article appeared on August 23, 2005

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Submitted on December 22, 2004
Revised on April 6, 2005
Accepted on May 10, 2005

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

Janelle R. Keys PhD, Rui-Hai Zhou MD, David M. Harris PhD, Charles A. Druckman BS, and Andrea D. Eckhart PhD^*

From the Department of Surgery, Duke University Medical Center, Durham, NC (J.R.K.), and the Eugene Feiner Laboratory for Vascular Biology and Thrombosis, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pa (R.-H.Z., D.M.H., C.A.D., A.D.E.). Dr Keys is now at the Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.

^* To whom correspondence should be addressed. E-mail: andrea.eckhart{at}jefferson.edu.

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 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 G_i-signaling inhibition or chronic ₁AR inhibition after 7 days of CGP20712A, whereas the ₂AR antagonist ICI 118,551 was ineffective. ₁AR 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 ₁AR 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.

Key words: hypertension • vasculature • blood pressure • receptors, adrenergic, beta • receptors

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