Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice
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
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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Research Article Vascular biology

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 1

Ipr deletion in mPges-1–deficient male hyperlipidemic mice abrogates salt-evoked hypertension.

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Ipr deletion in mPges-1–deficient male hyperlipidemic mice abrogates sal...
(A and B) SBP in male hyperlipidemic mice and mutants fed a HSD was measured via telemetry. A HSD led to a rise in SBP in Ldlr–/– (Ldlr-KO) mice in a time-dependent pattern, during both the active (night) and resting (day) periods. Deletion of mPges-1 in Ldlr–/– mice augmented salt-evoked hypertension. By contrast, deletion of the Ipr restrained salt-evoked hypertension and abrogated the hypertensive phenotype in Ipr–/– mPges-1–/– Ldlr–/– mutant mice. A 4-way, repeated-measures ANOVA showed a significant effect of the Ipr, mPges-1, phase, and a few of the 2- and 4-way interactions (Ipr:week, week:phase, Ipr:mPges-1:week:phase) on SBP. A post hoc pairwise t test showed a significant effect on SBP in week 2 with respect to baseline SBP for Ldlr–/– mice. (C and D) Similar trends in DBP responses were observed in both the active and resting periods in all mutant mice and their littermate controls fed a HSD. A 4-way, repeated-measures ANOVA showed a significant effect of the Ipr, week, phase, and week:phase interaction on DBP. A pairwise t test showed a significant effect on DBP only by week 2 compared with baseline DPB for Ldlr–/– mice. A pairwise t test was used to determine significant differences between Ldlr–/–, Ipr–/– mPges-1–/– Ldlr–/–, Ipr–/– Ldlr–/– (double-KO [DKO]), and mPges-1–/– Ldlr–/– mice. Genotypes and feeding periods with the same lowercase letter were significantly different (a–j, P < 0.05) at baseline, 1 week on a HSD, or 2 weeks on a HSD. For example, a – the baseline SBP (active phase) of mPges-1–/– Ldlr–/– (DKO) mice was significantly elevated compared with that of Ldlr–/– mice and b – Ipr–/– Ldlr–/– mice; f – the SBP (active phase) of mPges-1–/– Ldlr–/– mice was significantly elevated after 2 weeks on a HSD compared with baseline SBP. Data are expressed as the mean ± SEM. n = 13–16 mice per genotype.