{"doi":"10.1172/jci136310","title":"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.","journal":"Journal of Clinical Investigation","year":2021,"id":211975,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":644304,"name":"Hu Meng","orcid":"0000-0003-2224-5431","position":1,"is_corresponding":false},{"id":757225,"name":"Seán T. Anderson","orcid":"0000-0003-1805-2485","position":2,"is_corresponding":false},{"id":388715,"name":"Dimitra Sarantopoulou","orcid":"0000-0002-1972-8865","position":3,"is_corresponding":false},{"id":471854,"name":"Soumita Ghosh","orcid":"0000-0002-2783-2750","position":4,"is_corresponding":false},{"id":72462,"name":"Nicholas F. Lahens","orcid":"0000-0002-3965-5624","position":5,"is_corresponding":false},{"id":232872,"name":"Katherine N. Theken","orcid":"0000-0001-9918-9170","position":6,"is_corresponding":false},{"id":34965,"name":"Emanuela Ricciotti","orcid":"0000-0002-6971-3215","position":7,"is_corresponding":false},{"id":757223,"name":"Elizabeth J. Hennessy","orcid":"0000-0002-1231-5777","position":8,"is_corresponding":false},{"id":322004,"name":"Vincent Tu","orcid":null,"position":9,"is_corresponding":false},{"id":49754,"name":"Kyle Bittinger","orcid":"0000-0003-3472-5934","position":10,"is_corresponding":false},{"id":802361,"name":"Aalim M. Weiljie","orcid":null,"position":11,"is_corresponding":false},{"id":72468,"name":"Gregory R. Grant","orcid":"0000-0002-0139-7658","position":12,"is_corresponding":false},{"id":34970,"name":"Garret A. FitzGerald","orcid":"0000-0002-5885-6819","position":13,"is_corresponding":false},{"id":399320,"name":"Soon Yew Tang","orcid":"0000-0001-8364-0342","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:52:23.670339Z","pmid":"34101620","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}