EP3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation in a Mouse Model of Salt-Sensitive Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2021-04, Vol.77 (4), p.1399-1411
• Main Authors: Wu, Jing, Fang, Shi, Lu, Ko-Ting, Wackman, Kelsey, Schwartzman, Michal L., Dikalov, Sergey I., Grobe, Justin L., Sigmund, Curt D.
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Hypertension - metabolism; Hypertension - physiopathology; Kidney - blood supply; Mice; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiopathology; Oxidative Stress; PPAR gamma - metabolism; Receptors, Prostaglandin E, EP3 Subtype - metabolism; Signal Transduction; Sodium Chloride - metabolism; Vascular Resistance - physiology; Vasodilation - immunology; Vasodilation - physiology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.120.16518

We previously showed that impaired vasodilation in systemic and renal vessels contributes to salt-sensitive hypertension in a mouse model of impaired PPARγ (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 PPARγ 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 PPARγ 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 PPARγ activity.