Abstract

Cardiovascular regulation is tightly controlled by signaling through G protein-coupled receptors (GPCRs). β-Adrenergic receptors (ARs) are GPCRs that regulate inotropy and chronotropy in the heart and mediate vasodilation, which critically influences systemic vascular resistance. GPCR kinases (GRKs), including GRK2 (or βARK1), phosphorylate and desensitize agonist-activated βARs. Myocardial GRK2 levels are increased in heart failure and data suggest that vascular levels may also be elevated in hypertension. Therefore, we generated transgenic mice with vascular smooth muscle (VSM) targeted overexpression of GRK2, using a portion of the SM22α promoter, to determine its impact on vascular βAR regulation. VSM βAR signaling, as determined by adenylyl cyclase and mitogen-activated protein (MAP) kinase activation assays, was attenuated when GRK2 was overexpressed 2- to 3-fold. In vivo vasodilation in response to βAR stimulation using isoproterenol was attenuated and conscious resting mean arterial blood pressure was elevated from 96 ± 2 mm Hg in nontransgenic littermate control (NLC) mice (n = 9) to 112 ± 3 mm Hg and 117 ± 2 mm Hg in two different lines of SM22α-GRK2 transgenic mice (n = 7 and n = 5, respectively; p < 0.05). Interestingly, medial VSM thickness was increased 30% from 29.8 ± 1.6 μm in NLC mice (n = 6) to 39.4 ± 1.6 μm in SM22α-GRK2 mice (n = 7) (p < 0.05) and vascular GRK2 overexpression was sufficient to cause cardiac hypertrophy. These data indicate that we have developed a unique mouse model of hypertension, providing insight into the contribution that vascular βAR signaling makes toward resting blood pressure and overall cardiovascular regulation. Moreover, they suggest that GRK2 plays an important role in vascular control and may represent a novel therapeutic target for hypertension.