{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T22:09:05Z","timestamp":1775772545732,"version":"3.50.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070265"],"award-info":[{"award-number":["82070265"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023MH377"],"award-info":[{"award-number":["ZR2023MH377"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be elucidated. This study investigated the effects of PTE on monocrotaline (MCT)-induced PAH in rats <jats:italic>in vivo<\/jats:italic> and explored the underlying molecular mechanisms in human primary pulmonary arterial endothelial cells (hPAECs) <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Experimental PAH was established by subcutaneous injection of MCT (50\u00a0mg\/kg) in Sprague-Dawley rats, which were then randomly divided into vehicle or PTE (15\u00a0mg\/kg via gavage) treatment groups. Endothelial-to-mesenchymal transition (EndMT) was modeled in hPAECs by treating with transforming growth factor-\u03b2, tumor necrosis factor-\u03b1, and interleukin-1\u03b2 in combination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In rats with MCT-induced PAH, administration of PTE resulted in a reduction in right ventricular systolic pressure, thereby alleviating right ventricular hypertrophy. This was accompanied by mitigation of the remodeling of pulmonary arteries. <jats:italic>In vitro<\/jats:italic>, genome-wide mRNA sequencing identified that PTE significantly downregulated the expression of high mobility group AT-hook 2 (HMGA2), a transcription factor involved in the pathogenesis of EndMT. Further, we demonstrated that PTE attenuated EndMT-related changes, including (1) reduced expression of the endothelial cell-specific markers platelet and endothelial cell adhesion molecule 1, and von Willebrand factor; (2) reduced nitric oxide production; and (3) increased expression of smooth muscle \u03b1-actin and other pro-fibrotic genes. Finally, we confirmed <jats:italic>in vivo<\/jats:italic> that PTE treatment reduced the expression of HMGA1\/2 and Snai1\/2 (markers of EndMT), and restored the expression of von Willebrand factor in the lungs of PAH rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PTE mitigates MCT-induced PAH and vascular remodeling in rats, at least in part, by inhibiting HMGA-mediated EndMT, suggesting that PTE may be a useful complementary medicine in the treatment of PAH.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1621700","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T05:25:05Z","timestamp":1750829105000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Pterostilbene mitigates experimental pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition"],"prefix":"10.3389","volume":"16","author":[{"given":"Jie","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaopei","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weida","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"792","DOI":"10.3390\/ijms19030792","article-title":"Biological activities of stilbenoids","volume":"19","author":"Akinwumi","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1161\/atvbaha.121.313788","article-title":"Endothelial-mesenchymal transition in cardiovascular disease","volume":"41","author":"Alvandi","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3173","DOI":"10.1038\/onc.2010.92","article-title":"TWISTing an embryonic transcription factor into an oncoprotein","volume":"29","author":"Ansieau","year":"2010","journal-title":"Oncogene"},{"key":"B4","doi-asserted-by":"publisher","first-page":"L1","DOI":"10.1152\/ajplung.00378.2006","article-title":"Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension","volume":"293","author":"Arciniegas","year":"2007","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.14670\/hh-26.1029","article-title":"Upregulation of the high mobility group AT-hook 2 gene in acute aortic dissection is potentially associated with endothelial-mesenchymal transition","volume":"26","author":"Belge","year":"2011","journal-title":"Histol. Histopathol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1309739","DOI":"10.3389\/fimmu.2024.1309739","article-title":"Identification of a distinct cluster of GDF15(high) macrophages induced by in vitro differentiation exhibiting anti-inflammatory activities","volume":"15","author":"Dai","year":"2024","journal-title":"Front. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.cellsig.2016.02.011","article-title":"A crosstalk between TGF-\u03b2\/Smad3 and Wnt\/\u03b2-catenin pathways promotes vascular smooth muscle cell proliferation","volume":"28","author":"DiRenzo","year":"2016","journal-title":"Cell Signal"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3302","DOI":"10.1111\/bph.13948","article-title":"Pterostilbene reduces oxidative stress, prevents hypertrophy and preserves systolic function of right ventricle in cor pulmonale model","volume":"174","author":"Dos Santos Lacerda","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/s00109-019-01870-1","article-title":"Deletion of FHL2 in fibroblasts attenuates fibroblasts activation and kidney fibrosis via restraining TGF-\u03b21-induced Wnt\/\u03b2-catenin signaling","volume":"98","author":"Duan","year":"2020","journal-title":"J. Mol. Med. Berl."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1016\/j.ajpath.2015.03.019","article-title":"Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension","volume":"185","author":"Good","year":"2015","journal-title":"Am. J. Pathol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1089\/ars.2020.8169","article-title":"Endothelial-to-Mesenchymal transition in pulmonary arterial hypertension","volume":"34","author":"Gorelova","year":"2021","journal-title":"Antioxid. Redox Signal"},{"key":"B12","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ejphar.2018.10.008","article-title":"Pterostilbene alleviates fructose-induced renal fibrosis by suppressing TGF-\u03b21\/TGF-\u03b2 type I receptor\/Smads signaling in proximal tubular epithelial cells","volume":"842","author":"Gu","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0378-1119(00)00371-1","article-title":"Snail\/slug family of repressors: slowly going into the fast lane of development and cancer","volume":"257","author":"Hemavathy","year":"2000","journal-title":"Gene"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1161\/circulationaha.115.020617","article-title":"In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug","volume":"133","author":"Hopper","year":"2016","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"71","DOI":"10.2174\/1566524018666180705104844","article-title":"HMGA2 modulates the TGF\u03b2\/Smad, TGF\u03b2\/ERK and notch signaling pathways in human lens epithelial-mesenchymal transition","volume":"18","author":"Hou","year":"2018","journal-title":"Curr. Mol. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.vph.2008.06.003","article-title":"Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension","volume":"49","author":"Humbert","year":"2008","journal-title":"Vasc. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1097\/00005344-199707000-00018","article-title":"Bioactivation of monocrotaline by P-450 3A in rat liver","volume":"30","author":"Kasahara","year":"1997","journal-title":"J. Cardiovasc Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"12836","DOI":"10.1021\/acs.jafc.0c00070","article-title":"Chemistry of pterostilbene and its metabolic effects","volume":"68","author":"Kim","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1159\/000489154","article-title":"AMPK contributes to cardioprotective effects of pterostilbene against myocardial ischemia- reperfusion injury in diabetic rats by suppressing cardiac oxidative stress and apoptosis","volume":"46","author":"Kosuru","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1080\/10715762.2018.1506115","article-title":"Stilbenoid pterostilbene complexed with cyclodextrin preserves left ventricular function after myocardial infarction in rats: possible involvement of thiol proteins and modulation of phosphorylated GSK-3\u03b2","volume":"52","author":"Lacerda","year":"2018","journal-title":"Free Radic. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1139\/apnm-2019-0864","article-title":"Pterostilbene improves cardiac function in a rat model of right heart failure through modulation of calcium handling proteins and oxidative stress","volume":"45","author":"Lacerda","year":"2020","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1074\/jbc.RA117.000295","article-title":"Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium","volume":"293","author":"Lee","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"121223","DOI":"10.1016\/j.lfs.2022.121223","article-title":"Exosomal circ-1199 derived from EPCs exposed to oscillating shear stress acts as a sponge of let-7g-5p to promote endothelial-mesenchymal transition of EPCs by increasing HMGA2 expression","volume":"312","author":"Li","year":"2023","journal-title":"Life Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/s41419-019-2101-4","article-title":"MKL1 promotes endothelial-to-mesenchymal transition and liver fibrosis by activating TWIST1 transcription","volume":"10","author":"Li","year":"2019","journal-title":"Cell Death Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"H2331","DOI":"10.1111\/1750-3841.13002","article-title":"Pterostilbene inhibits vascular smooth muscle cells migration and matrix metalloproteinase-2 through modulation of MAPK pathway","volume":"80","author":"Lin","year":"2015","journal-title":"J. Food Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.2174\/13816128113199990512","article-title":"Epigenetic regulation of EMT: the Snail story","volume":"20","author":"Lin","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"B27","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.yjmcc.2019.09.004","article-title":"The axis of local cardiac endogenous Klotho-TGF-\u03b21-Wnt signaling mediates cardiac fibrosis in human","volume":"136","author":"Liu","year":"2019","journal-title":"J. Mol. Cell Cardiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.humimm.2021.11.006","article-title":"The role of immune cells in pulmonary hypertension: focusing on macrophages","volume":"83","author":"Luo","year":"2022","journal-title":"Hum. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1002\/cphy.c200025","article-title":"Inflammatory mechanisms in the pathogenesis of pulmonary arterial hypertension: recent advances","volume":"11","author":"Mercurio","year":"2021","journal-title":"Compr. Physiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"6316","DOI":"10.3390\/molecules27196316","article-title":"New insights into dietary pterostilbene: sources, metabolism, and Health promotion effects","volume":"27","author":"Nagarajan","year":"2022","journal-title":"Molecules"},{"key":"B31","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.vph.2010.04.001","article-title":"Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway","volume":"53","author":"Park","year":"2010","journal-title":"Vasc. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/s11130-015-0488-3","article-title":"Pterostilbene, an active constituent of blueberries, stimulates nitric oxide production via activation of endothelial nitric oxide synthase in human umbilical vein endothelial cells","volume":"70","author":"Park","year":"2015","journal-title":"Plant Foods Hum. Nutr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1007\/s40203-024-00211-6","article-title":"Comparative analyses of anti-inflammatory effects of Resveratrol, Pterostilbene and Curcumin: in-silico and in-vitro evidences","volume":"12","author":"Patil","year":"2024","journal-title":"In Silico Pharmacol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1093\/carcin\/bgq004","article-title":"Dietary intake of pterostilbene, a constituent of blueberries, inhibits the beta-catenin\/p65 downstream signaling pathway and colon carcinogenesis in rats","volume":"31","author":"Paul","year":"2010","journal-title":"Carcinogenesis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13020-021-00474-7","article-title":"Pterostilbene alleviates pulmonary fibrosis by regulating ASIC2","volume":"16","author":"Peng","year":"2021","journal-title":"Chin. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1161\/circulationaha.114.008750","article-title":"Endothelial-to-mesenchymal transition in pulmonary hypertension","volume":"131","author":"Ranchoux","year":"2015","journal-title":"Circulation"},{"key":"B37","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.bbcan.2018.03.001","article-title":"High Mobility Group A (HMGA) proteins: molecular instigators of breast cancer onset and progression","volume":"1869","author":"Sgarra","year":"2018","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"L1013","DOI":"10.1152\/ajplung.00217.2009","article-title":"Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure","volume":"297","author":"Stenmark","year":"2009","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"7134","DOI":"10.1074\/jbc.M111.291385","article-title":"Regulation of transcription factor Twist expression by the DNA architectural protein high mobility group A2 during epithelial-to-mesenchymal transition","volume":"287","author":"Tan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"L256","DOI":"10.1152\/ajplung.00096.2017","article-title":"Endothelial HIF-2\u03b1 contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition","volume":"314","author":"Tang","year":"2018","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"33437","DOI":"10.1074\/jbc.M802016200","article-title":"HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition","volume":"283","author":"Thuault","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1083\/jcb.200512110","article-title":"Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition","volume":"174","author":"Thuault","year":"2006","journal-title":"J. Cell Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s00441-016-2539-y","article-title":"Pulmonary vascular remodeling in pulmonary hypertension","volume":"367","author":"Tuder","year":"2017","journal-title":"Cell Tissue Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"654","DOI":"10.3390\/ijms21020654","article-title":"HMGA genes and proteins in development and evolution","volume":"21","author":"Vignali","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"106238","DOI":"10.1016\/j.phrs.2022.106238","article-title":"Immunity and inflammation in pulmonary arterial hypertension: from pathophysiology mechanisms to treatment perspective","volume":"180","author":"Wang","year":"2022","journal-title":"Pharmacol. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1007\/s10787-024-01440-z","article-title":"Pterostilbene: a potential therapeutic agent for fibrotic diseases","volume":"32","author":"Wang","year":"2024","journal-title":"Inflammopharmacology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"12752","DOI":"10.1021\/acs.jafc.9b05373","article-title":"Pterostilbene attenuates experimental atherosclerosis through restoring catalase-mediated redox balance in vascular smooth muscle cells","volume":"67","author":"Wang","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"436","DOI":"10.3389\/fcell.2020.00436","article-title":"Induction of autophagy by pterostilbene contributes to the prevention of renal fibrosis via attenuating NLRP3 inflammasome activation and epithelial-mesenchymal transition","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1111\/bph.15385","article-title":"Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling","volume":"178","author":"Xu","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.3390\/molecules23051148","article-title":"Pterostilbene and 4'-methoxyresveratrol inhibited lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages","volume":"23","author":"Yao","year":"2018","journal-title":"Molecules"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1021\/jm101248v","article-title":"Fluorinated N,N-dialkylaminostilbenes for Wnt pathway inhibition and colon cancer repression","volume":"54","author":"Zhang","year":"2011","journal-title":"J. Med. Chem."},{"key":"B53","doi-asserted-by":"publisher","first-page":"155696","DOI":"10.1016\/j.phymed.2024.155696","article-title":"Targeting the smooth muscle cell KEAP1-Nrf2-STING axis with pterostilbene attenuates abdominal aortic aneurysm","volume":"130","author":"Zou","year":"2024","journal-title":"Phytomedicine"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1621700\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T05:25:08Z","timestamp":1750829108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1621700\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":53,"alternative-id":["10.3389\/fphar.2025.1621700"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1621700","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,25]]},"article-number":"1621700"}}