{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:06:23Z","timestamp":1784696783729,"version":"3.55.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Introduction<\/jats:title>\n Hypoxic pulmonary hypertension (HPH), a severe complication of chronic obstructive pulmonary disease, features pulmonary vascular remodeling driven by dysregulated pulmonary arterial smooth muscle cell (PASMC) apoptosis, with limited therapies like vasodilators offering only modest hemodynamic benefits. This study aimed to elucidate the role of Midkine (MK) in regulating PASMC apoptosis via the Notch2 pathway and its potential as a novel anti-remodeling target in HPH progression.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n The experimental approach involved cellular and animal models.\n In vitro<\/jats:italic>\n , PASMCs were exposed to hypoxia (1% O\n 2<\/jats:sub>\n , 48\u00a0h), and MK was silenced via lentiviral shRNA (shRNA-413, \u223c85% knockdown). Cellular phenotypes were assessed using Cell Counting Kit-8 assays for proliferation, wound healing assays for migration, and flow cytometry for apoptosis. Molecular analyses (quantitative polymerase chain reaction and western blot) targeted apoptosis-related proteins and Notch2 signaling.\n In vivo<\/jats:italic>\n , HPH was induced in rats by LPS plus chronic hypoxia\/smoke exposure; MK was inhibited via intratracheal adeno-associated virus serotype 9-mediated gene delivery (AAV9-shRNA (1.5 \u00d7 10\n 11<\/jats:sup>\n vg\/rat). Outcomes included hemodynamics, vascular remodeling, oxidative stress markers, and apoptosis-related protein expression in lung tissue.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In vitro<\/jats:italic>\n , hypoxia upregulated MK, activating Notch2-Hes1 signaling, promoting proliferation and migration at 48\u00a0h, and suppressing apoptosis (\n P<\/jats:italic>\n &lt; 0.01 vs. normoxia). MK knockdown reversed these effects, restoring apoptosis (\n P<\/jats:italic>\n &lt; 0.01).\n In vivo<\/jats:italic>\n , HPH activated the MK-Notch2 axis in rat lung tissue; MK suppression inhibited Notch2 signaling, improved antioxidant capacity, alleviated oxidative stress (e.g., elevated SOD\/CAT, reduced MDA\/LDH;\n P<\/jats:italic>\n &lt; 0.01), induced PASMC apoptosis, attenuated vascular remodeling, and reduced pulmonary arterial pressure.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Unlike current vasodilators, MK drives HPH pathogenesis by suppressing PASMC apoptosis via Notch2 and exacerbating oxidative stress. Targeting MK offers a promising therapeutic strategy for HPH.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2026.1788582","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:44:19Z","timestamp":1784695459000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic investigation of Midkine-Notch2 signaling in suppressing pulmonary artery smooth muscle cell apoptosis and promoting vascular remodeling in hypoxic pulmonary hypertension"],"prefix":"10.3389","volume":"17","author":[{"given":"Houfan","family":"Zhu","sequence":"first","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binglong","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunkai","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Radiology, Hainan Modern Women and Children\u2019s Hospital","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangpeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Liao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengchao","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Zhong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiyun","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tang","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4809","DOI":"10.3390\/ijms26104809","article-title":"Significance of midkine signaling in women\u2019s cancers: novel biomarker and therapeutic target","volume":"26","author":"Aller","year":"2025","journal-title":"Int. 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