Abstract 15692: Low Blood Pressure And Defective Vasoconstriction In Tie2-cre/grk2fl/fl mice
GRK2 regulates eNOS activity through Akt binding and inhibition in endothelial cells derived from liver sinusoidal capillaries. However, the role of GRK2 in regulation of systemic vascular tone has not been explored yet. We generated mice with selective genetic ablation of GRK2 in the endothelium (Tie2-CRE/GRK2fl/fl ). We observed that invasive unconscious systemic pressure was reduced in the Tie2-CRE/GRK2fl/fl compared to GRK2fl/fl mice used as controls (95/60±3/3 vs 130/85±4/5 mmHg, p<0,05). Isolated, perfused Tie2-CRE/GRK2fl/fl aortas connected to a pressure transducer exhibited a dramatic reduction of vasoconstriction stimulated by receptor agonists Phenylephrine (Phe 10-6 M: 283±52vs10±7 mg, p<0,05), Serotonin (Ser 10-6 M : 173±10vs20±14 mg, p<0,05 ) and Oxytocin (Oss 10-7 M : 150±48vs20±14 mg, p<0,05), and to receptor independent vasoconstriction induced by KCl (12.5 mM: 195±61vs38±23* mg, p<0,05). Accordingly, we hypothesized that lack of endothelial GRK2 increases eNOS activity, enhancing vasodilatation. Indeed, partial recovery of vasoconstriction was observed in endothelium-denuded Tie2-CRE/GRK2fl/fl aortas (Phe:152±28, Ser:112±22, Oss:100±29, KCl:115±12 mg vs Tie2-CRE/GRK2fl/fl with endothelium, p<0,005). Histology and immunohistochemistry reveal structural modifications of the Tie2-CRE/GRK2fl/fl media which is accompanied by macrophages infiltration, compared to GRK2fl/fl (Figure), explaining the incomplete recovery of vasoconstriction even when endothelium is removed. Our data suggest that endothelial GRK2 is pivotal to fine regulation of eNOS activity, thus participating to the control of vascular tone and blood pressure homeostasis.
- © 2011 by American Heart Association, Inc.