Phosphodiesterases Mediate the Augmentation of Myogenic Constriction by Inhibitory G Protein Signaling and is Negatively Modulated by the Dual Action of RGS2 and 5

G protein regulation by regulators of G protein signaling (RGS) proteins play a key role in vascular tone maintenance. The loss of G and G regulation by RGS2 and RGS5 in non-pregnant mice is implicated in augmented vascular tone and decreased uterine blood flow (UBF). RGS2 and 5 are closely related and co-expressed in uterine arteries (UA). However, whether and how RGS2 and 5 coordinate their regulatory activities to finetune G protein signaling and regulate vascular tone are unclear. Here, we determined how the integrated activity of RGS2 and 5 modulates vascular tone to promote UBF. Using ultrasonography and pressure myography, we examined uterine hemodynamics and myogenic tone (MT) of UA of wild type (WT), , and dbKO mice. We found that MT was reduced in relative to WT or UA. Activating G with dopamine increased, whereas exogenous cAMP decreased MT in UA to levels in WT UA. Dual deletion of and abolished the reduced MT due to the absence of and enhanced dopamine-induced G effects in dbKO UA. Conversely, and as in WT UA, G inhibition with pertussis toxin or exogenous cAMP decreased MT in dbKO to levels in UA. Inhibition of phosphodiesterases (PDE) concentration-dependently decreased and normalized MT in all genotypes, and blocked dopamine-induced MT augmentation in , and dbKO UA. We conclude that G augments UA MT in the absence of RGS2 by a novel mechanism involving PDE-mediated inhibition of cAMP-dependent vasodilatation..