Osei-Owusu Lab publishes 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_i/o and G_q/11 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), Rgs2^-/-, Rgs5^-/-, and Rgs2/5 dbKO mice. We found that MT was reduced in Rgs5^-/- relative to WT or Rgs2^-/- UA. Activating G_i/o with dopamine increased, whereas exogenous cAMP decreased MT in Rgs5^-/- UA to levels in WT UA. Dual deletion of Rgs2 and 5 abolished the reduced MT due to the absence of Rgs5 and enhanced dopamine-induced G_i/o effects in Rgs2/5 dbKO UA. Conversely, and as in WT UA, G_i/o inhibition with pertussis toxin or exogenous cAMP decreased MT in Rgs2/5 dbKO to levels in Rgs5^-/- UA. Inhibition of phosphodiesterases (PDE) concentration-dependently decreased and normalized MT in all genotypes, and blocked dopamine-induced MT augmentation in Rgs2^-/-, Rgs5^-/-, and Rgs2/5 dbKO UA. We conclude that G_i/o augments UA MT in the absence of RGS2 by a novel mechanism involving PDE-mediated inhibition of cAMP-dependent vasodilatation..