Ep3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation In A Mouse Model Of Salt-Sensitive Hypertension

We previously showed that impaired vasodilation in systemic and renal vessels contributes to salt-sensitive hypertension in a mouse model of impaired PPAR gamma (peroxisome proliferator-activated receptor gamma) function. We determined the mechanisms mediating impaired salt-induced vasodilation and whether improved vasodilation attenuates augmented hypertension in response to salt. Mice selectively expressing a PPAR gamma dominant negative mutation in vascular smooth muscle (S-P467L) exhibited salt-sensitive hypertension and severely impaired vasodilation in systemic and renal vessels. High-salt diet-fed S-P467L and control mice displayed comparable levels of renal oxidative stress markers. Preincubation with Tempol, a superoxide dismutase mimetic, or calphostin C, a PKC (protein kinase C) inhibitor, failed to improve salt-induced impairment of vasodilation in S-P467L mice, arguing against a role of oxidative stress or PKC activity. Inhibition of Rho kinase partially rescued impaired vasodilation in high-salt diet-fed S-P467L mice suggesting a contribution of the Ras homolog family member A (RhoA)/Rho kinase pathway. High-salt diet selectively increased synthesis of PGE2 (prostaglandin E2) in S-P467L aorta. Expression of EP3 (E-prostanoid 3) receptor mRNA was increased in aorta from chow-fed and high salt-fed S-P467L mice. Pharmacological inhibition of COX (cyclooxygenase) 2 or blockade of EP3 completely normalized the impaired vasodilation, and EP3 antagonism induced larger decreases in systolic blood pressure in high-salt diet-fed S-P467L mice. In conclusion, interference with PPAR gamma in vascular smooth muscle causes activation of the PGE2/EP3 signaling pathway in systemic and renal vasculature resulting in salt-induced impairment of vasodilation and salt-sensitive hypertension. PGE2/EP3 axis maybe a druggable target to prevent salt-sensitive hypertension in chronic conditions associated with decreased PPAR gamma activity.