Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

Abstract

Inhibitors of mPges-1 are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing PGE 2 , but increasing biosynthesis of PGI 2 . In Ldlr -/mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE 2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on BP in this setting remains unknown. Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr -/mice, whereas, despite the direct vasodilator properties of PGI 2 , Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1 -/mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr -/mice and in Ipr -/-/Ldlr -/mice. Thus, estrogen compensates for a deficiency in PGI 2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.

Prostanoids in Cardiac and Vascular Remodeling

“…80,97 In response to HSD, IPr KO mice may present increased or reduced BP, depending on the experimental conditions. 78,[98][99][100] Iloprost mediates endothelium-dependent relaxations in the mouse vasculature via the activation of cGMP and cAMP pathways. 101 Beraprost prevents vascular stiffness in elderly with cerebral infarction.…”