GRK2 targeted knock-down results in spontaneous hypertension, and altered vascular GPCR signaling.

G Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure

“…In small hairpin Grk2 knockdown mice, for example, both phenylephrine-induced contractile responses and isoproterenol-mediated vasodilation are increased; which one dominates would eventually determine the physiological phenotype. 22 After inhibition of GRK2 by either peptide inhibition or gene ablation, downregulation of GRK2 does not only increase b-AR-mediated vasodilation but also enhances a 1D -AR-stimulated vasoconstriction and could explain the lack of effect on blood pressure of a decrease in GRK2 expression or function. 35 Whether or not the discrepant results could be related to sex differences were not determined, but the small hairpin Grk2 studies were performed only in male mice because the Grk2 small hairpin RNA transgene was incorporated into the Y chromosome 22 ; the sexes of the mice in the other studies were not given.…”

“…22 After inhibition of GRK2 by either peptide inhibition or gene ablation, downregulation of GRK2 does not only increase b-AR-mediated vasodilation but also enhances a 1D -AR-stimulated vasoconstriction and could explain the lack of effect on blood pressure of a decrease in GRK2 expression or function. 35 Whether or not the discrepant results could be related to sex differences were not determined, but the small hairpin Grk2 studies were performed only in male mice because the Grk2 small hairpin RNA transgene was incorporated into the Y chromosome 22 ; the sexes of the mice in the other studies were not given. Nevertheless, the transgenic overexpression of GRK5 in vascular smooth muscle increases blood pressure to a greater extent in male than in female mice.…”

“…Accordingly, except for GRK1 and GRK7, other GRK members (GRK2-6) exert different physiological effects, specifically, the regulation of blood pressure by the cardiovascular system and the kidney. [8][9][10][11][16][17][18][20][21][22][23][24] G protein-coupled receptor kinase 2…”

“…40 Consequently, deletion of GRK2 should result in a decrease in blood pressure; However, global knockdown of Grk2 expression using small hairpin interfering RNA in male mice produces hypertension that is associated with vascular remodeling caused in part by increases in cell proliferation at age 6 months but not at 3 months. 22 The causes of the differences are not known, but the differential effects of GRK2 on vasoconstriction and vasodilation may explain this apparently conflicting results. In small hairpin Grk2 knockdown mice, for example, both phenylephrine-induced contractile responses and isoproterenol-mediated vasodilation are increased; which one dominates would eventually determine the physiological phenotype.…”

“…Impairs b-AR induced vasodilation 34 ; increases resting blood pressure 34 Increased GRK2 expression and GRK activity in lymphocytes and arteries in hypertensive patients and SHRs 60,63,64 ; increased GRK2 expression in conductance and resistance vessels in SHRs 61,117 ; decreased GRK2 expression in conductance vessels and no change in GRK2 expression in resistance vessels in L-NAME-induced hypertensive rats 61 ; increased GRK2 expression and GRK activity in mesenteric artery of sedentary SHRs 43 ; increased renal GRK2 expression in obese rats 29 ; increased renal GRK2 expression in offspring of lipopolysaccharide-treated dams 57 Hemizygous mice (GRK2 +/À ) No effect on baseline blood pressure but protects against Ang II-induced hypertension and vascular remodeling 33 Global knockdown using a shRNA Results in spontaneous hypertension 22 ; increases both vasoconstriction in response to PE and vasodilatation in response to b-AR stimulation 22…”