{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:39:25Z","timestamp":1790314765708,"version":"4.1.0"},"reference-count":92,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PAs) and progressive increase in pulmonary vascular resistance leading to right ventricular failure. Although several drugs are approved for the treatment of PAH, mortality rates remain high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>The expression of the RGD (arginylglycylaspartic acid)\u2013binding integrin \u03b15\u03b21 was assessed in PAs, PA smooth muscle cells, and PA endothelial cells from patients with PAH and controls using NanoString, immunoblotting, and Mesoscale Discovery assays. RNA sequencing was conducted to identify gene networks regulated by \u03b15\u03b21 inhibition in PAH PA smooth muscle cells. The therapeutic efficacy of \u03b15\u03b21 inhibition was evaluated using a novel small molecule inhibitor and selective neutralizing antibodies in Sugen\/hypoxia and monocrotaline rat models, with validation by an external contract research organization. Comparisons were made against standard-of-care therapies (ie, macitentan, tadalafil) and sotatercept and efficacy was assessed using echocardiographic, hemodynamic, and histological assessments. Ex vivo studies using human precision-cut lung slices were performed to further assess the effects of \u03b15\u03b21 inhibition on pulmonary vascular remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>We found that the arginine-glycine-aspartate RGD-binding integrin \u03b15\u03b21 is upregulated in PA endothelial cells and PA smooth muscle cells from patients with PAH and remodeled PAs from animal models. Blockade of the integrin \u03b15\u03b21 or depletion of the \u03b15 subunit downregulated FOXM1 (forkhead box protein M1)\u2013regulated gene networks, resulting in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. We demonstrated that \u03b15\u03b21 integrin blockade safely attenuates pulmonary vascular remodeling and improves hemodynamics and right ventricular function and matched or exceeded the efficacy of standard of care and sotatercept in multiple preclinical models. Ex vivo studies further validated its potential in reversing advanced remodeling in human precision-cut lung slices.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings establish \u03b15\u03b21 integrin as a pivotal driver of PAH pathology and we propose its inhibition as a novel, safe, and effective therapeutic strategy for PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.070693","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T05:00:26Z","timestamp":1737349226000},"page":"1162-1183","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Exploring Integrin \u03b15\u03b21 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies"],"prefix":"10.1161","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6625-9918","authenticated-orcid":true,"given":"Sarah-Eve","family":"Lemay","sequence":"first","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica S.","family":"Montesinos","sequence":"additional","affiliation":[{"name":"Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3200-3241","authenticated-orcid":true,"given":"Yann","family":"Grobs","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8197-3274","authenticated-orcid":true,"given":"Tetsuro","family":"Yokokawa","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.)."},{"name":"Department of Cardiovascular Medicine, Fukushima Medical University, Japan (T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9834-4770","authenticated-orcid":true,"given":"Tsukasa","family":"Shimauchi","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.)."},{"name":"Department of Anesthesiology, St Mary\u2019s Hospital, Kurume, Fukuoka, Japan (T.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Mougin","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3583-2758","authenticated-orcid":true,"given":"Charlotte","family":"Romanet","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., 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