Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice
Soon Y. Tang, … , Gregory R. Grant, Garret A. FitzGerald
Soon Y. Tang, … , Gregory R. Grant, Garret A. FitzGerald
Published June 8, 2021
Citation Information: J Clin Invest. 2021;131(14):e136310. https://doi.org/10.1172/JCI136310.
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Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

Abstract

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 E2 (PGE2), but increasing the biosynthesis of prostacyclin (PGI2). 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 PGE2 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 PGI2, 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 PGI2 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.

Authors

Soon Y. Tang, Hu Meng, Seán T. Anderson, Dimitra Sarantopoulou, Soumita Ghosh, Nicholas F. Lahens, Katherine N. Theken, Emanuela Ricciotti, Elizabeth J. Hennessy, Vincent Tu, Kyle Bittinger, Aalim M. Weiljie, Gregory R. Grant, Garret A. FitzGerald

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Figure 5

The ANP receptor antagonist A71915 and estrogen mediate salt-evoked BP responses in Ipr-deficient male and female hyperlipidemic mice, respectively.

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The ANP receptor antagonist A71915 and estrogen mediate salt-evoked BP r...
The ANP antagonist A71915 rescued hypotension in Ipr–/– Ldlr–/– mice fed a HSD. SBPs during (A) the active phase (7 pm–9 pm) and (B) the resting phase (7 am–9 am) for male mice with and without minipumps were measured using a tail-cuff system before and 1 and 2 weeks after HSD feeding in conjunction with or without ANP inhibition via A71915 infusion (50 μg/kg BW/day). To compare the effect of Ipr deletion and A71915 administration, genotype and feeding times with the same lowercase letter denote significant differences (a–g, P < 0.05) after 1 week on a HSD or after 2 weeks on a HSD. For example, a – the SBP (active phase) of Ipr–/– Ldlr–/– mice was significantly elevated after 1 week on a HSD and b – after 2 weeks on a HSD compared with baseline SBP; d – the SBP (active phase) of Ldlr–/– mice was significantly elevated compared with the SBP of Ipr–/– Ldlr–/– mice after 1 week on a HSD, etc. Data are expressed as the mean ± SEM. n = 8–10 mice per group. (C–F) Salt loading increased BP in OVX Ldlr–/– and Ipr–/– Ldlr–/– mice. E2 replacement restrained the BP responses. To compare the effect of Ipr deletion and E2 administration, genotype and/or feeding time with the same lowercase letter were significantly different (a–f, P < 0.05) after 1 week on a HSD or after 2 weeks on a HSD. For example, a – the SBP (active phase) of Ipr Ldlr-DKO mice treated with vehicle (veh) was significantly higher than the SBP of Ipr–/– Ldlr–/– mice treated with E2 after 1 week on a HSD and b – after 2 weeks on a HSD; c – the SBP (active phase) of Ipr–/– Ldlr–/– mice treated with vehicle was significantly higher after 1 week on a HSD compared with baseline SBP, etc. Data are expressed as the mean ± SEM. n = 6 –9 mice per group.