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Vol. 61, Issue 4, 749-758, April 2002
-Adrenergic Receptor
Signaling and Increases Resting Blood Pressure
Department of Surgery (A.D.E., H.T., W.J.K.) and
Department of Medicine (Cardiology) (T.O., H.A.R.), Duke University
Medical Center, Durham, North Carolina
Cardiovascular regulation is tightly controlled by signaling through G
protein-coupled receptors (GPCRs). 
-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 ARK1), phosphorylate and
desensitize agonist-activated ARs. 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 SM22
promoter, to determine its impact on
vascular AR regulation. VSM AR 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 AR 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 SM22-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 SM22-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 AR 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.
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