{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:20:59Z","timestamp":1792794059691,"version":"4.5.0"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["HL159037"],"award-info":[{"award-number":["HL159037"]}]},{"name":"NIH","award":["2R25 GM121212-06"],"award-info":[{"award-number":["2R25 GM121212-06"]}]},{"name":"NIH","award":["AI177493"],"award-info":[{"award-number":["AI177493"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:p>\n                    Schistosomiasis-associated pulmonary hypertension (Sch-PH) is the most common form of group I PH worldwide. Recently, data revealed that the preclinical Sch-PH animal model exhibited gut and lung microbiome dysbiosis, associated with significant lung endothelial cell (EC) dysfunction and microvascular apoptosis. However, the role of pro-\/antiapoptosis sensors, such as the inhibitor of apoptosis protein 2 (c-IAP2) and the purinergic receptor P2X7 (P2X7R), remained unclear. Using Cdh5cre-ER\n                    <jats:sup>T2<\/jats:sup>\n                    ;cIAP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ;cIAP2\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    animal model, this study investigated the contribution of endothelial c-IAP2 in this process, revealing pulmonary P2X7R overexpression as a putative target in the onset of Sch-PH. Pharmacologically, inhibition of P2X7R function confirmed its role in promoting lung EC death and disease progression. Moreover, data suggest that microbiome-associated metabolic alterations in Sch-PH seem linked to microvascular EC apoptosis driven by ATP\/P2X7R overactivation and suppressed c-IAP2 expression. Indeed, genetic ablation of endothelial c-IAP2 expression was sufficient to induce PH-like features in mice, with echocardiography indicating a higher pulmonary acceleration time (PAT), PAT\/pulmonary ejection time, and right ventricular free wall thickness (RVFWTH) after IP\/IV-Egg challenge compared to controls, an effect linked to the female prevalence of the disease. These findings suggest a significant contribution of lung EC-P2X7R activation and c-IAP2 suppression to sex-linked Sch-PH pathology, highlighting them as promising therapeutic targets for this life-threatening illness.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513158123","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T19:02:12Z","timestamp":1781550132000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Endothelial c-IAP2 loss amplifies P2X7 receptor-driven inflammation and worsens schistosomiasis-associated pulmonary hypertension"],"prefix":"10.1073","volume":"123","author":[{"given":"Elizabeth Sue","family":"Villarreal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02mpq6x41","id-type":"ROR","asserted-by":"publisher"}],"name":"Vascular Immunobiology Lab, College of Medicine, Department of Anesthesiology, University of Illinois 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