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Recently, data revealed that the preclinical animal model of Sch-PH exhibited gut and lung microbiome dysbiosis linked to significant endothelial dysfunction and microvascular apoptosis, but the role of pro\/anti-apoptosis sensors, such as the inhibitor of apoptosis protein 2 (c-IAP2) and purinergic receptor P2X7 (P2X7R), remained unclear. Using a novel Cdh5cre-ER\n                  <jats:sup>T2<\/jats:sup>\n                  ;cIAP1\n                  <jats:sup>-\/-<\/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 P2X7R overexpression as a putative target in the onset of Sch-PH. Pharmacologically, inhibition of P2X7R function confirmed its role in promoting lung endothelial death and disease progression. Moreover, data suggest that microbiome-associated metabolic alterations in Sch-PH seem linked to microvascular endothelial 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 (PET), and right ventricular free wall thickness after IP\/IV-Egg challenge compared to controls. These findings suggest a significant contribution of lung endothelial P2X7R activation and c-IAP2 suppression to Sch-PH pathology, highlighting them as promising novel therapeutic targets for this life-threatening illness.\n                <\/jats:p>","DOI":"10.1101\/2025.05.22.655387","type":"posted-content","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T13:50:21Z","timestamp":1748353821000},"source":"Crossref","is-referenced-by-count":1,"title":["Endothelial c-IAP2 Loss Amplifies P2X7 Receptor-Driven Inflammation and Worsens Infection-Associated Pulmonary Hypertension"],"prefix":"10.64898","author":[{"given":"ES","family":"Villarreal","sequence":"first","affiliation":[{"name":"Vascular Immunobiology Lab; College of Medicine; Dept. of Anesthesiology - University of Illinois Chicago \u2013 IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Marinho","sequence":"additional","affiliation":[{"name":"Vascular Immunobiology Lab; College of Medicine; Dept. of Anesthesiology - University of Illinois Chicago \u2013 IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O","family":"Loya","sequence":"additional","affiliation":[{"name":"Vascular Immunobiology Lab; College of Medicine; Dept. of Anesthesiology - University of Illinois Chicago \u2013 IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SY","family":"Aboagye","sequence":"additional","affiliation":[{"name":"Dept. of Microbial Pathogens and Immunity - Rush University - IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DL","family":"Williams","sequence":"additional","affiliation":[{"name":"Dept. of Microbial Pathogens and Immunity - Rush University - IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7465-3133","authenticated-orcid":false,"given":"J","family":"Sun","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic Foundation, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Erzurum","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5532-8247","authenticated-orcid":false,"given":"V","family":"de Jesus Perez","sequence":"additional","affiliation":[{"name":"College of Medicine; Dept. of Medicine - University of Illinois Chicago \u2013 IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-1909","authenticated-orcid":false,"given":"SD","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Vascular Immunobiology Lab; College of Medicine; Dept. of Anesthesiology - University of Illinois Chicago \u2013 IL USA"},{"name":"Vascular Immunobiology Lab; College of Medicine; Dept. of Physiology and Biophysics - University of Illinois Chicago \u2013 IL USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041123400129000_2025.05.22.655387v1.1","first-page":"275","article-title":"Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension","volume":"144","year":"1994","journal-title":"Am. 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