Sex-Dependent Compensatory Mechanisms Preserve Blood Pressure Homeostasis In Prostacyclin Receptor-Deficient Mice

Inhibitors of microsomal prostaglandin E synthase 1 (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 prostaglandin E-2 (PGE(2)), but increasing the biosynthesis of prostacyclin (PGI(2)). In low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE(2) accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges(-1) depletion significantly increased the BP response to salt loading in male Ldlr(-/-) mice, whereas, despite the direct vasodilator properties of PGI(2), deletion of the I prostanoid receptor (Ipr) suppressed this response. 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 (HSD). 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 male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.