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Paeoniflorin (PF) is the main bioactive compound in the roots of Paeonia lactiflora Pall, which is commonly used to treat a range of cardiovascular disorders. However, the mechanisms underlying the ameliorating effects of PF on PAD remain unclear. Therefore, the purpose of this study was to explore the therapeutic efficiency of PF on PAD and determine its mechanisms. Methods: The blood flow of mice was detected with a laser Doppler dot scanning imaging system. HE staining was used to observe the morphological changes of ischemic muscle. The changes in the serologic indexes were detected with an automatic biochemical assay, and the capillary density of ischemic gastrocnemius was detected with a Lectin immunofluorescence assay. The expression of angiogenesis-related proteins in ischemic gastrocnemius was detected with Western blotting, and the proportion of macrophages and neutrophils in total cells was detected with flow cytometry. Results: PF significantly increased blood flow, capillary density and protein expressions of vascular endothelial growth factor A (VEGFA), matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 2 (MMP9), and estrogen receptor \u03b1 (ER\u03b1) in mouse ischemic tissue in a PAD model. PF enhances the migration of endothelial cells and promotes the formation of tubular structures, involving the ER\u03b1\/ROCK2 signaling pathway. Furthermore, PF was found to promote the phenotypic transformation of macrophages and alleviated grave inflammatory responses during vascular remodeling. Conclusions: We determined that PF as a potent compound in promoting angiogenesis and mitigating inflammatory responses during revascularization.<\/jats:p>","DOI":"10.3390\/ph18020272","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T08:36:46Z","timestamp":1739954206000},"page":"272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Paeoniflorin Attenuates Limb Ischemia by Promoting Angiogenesis Through ER\u03b1\/ROCK-2 Pathway"],"prefix":"10.3390","volume":"18","author":[{"given":"Mengyao","family":"Li","sequence":"first","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Instrumental Analysis and Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyun","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenkun","family":"Xu","sequence":"additional","affiliation":[{"name":"Instrumental Analysis and Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinze","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health and Health Sciences, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxia","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Instrumental Analysis and Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e347","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart Disease and Stroke Statistics: A Report of US and Global Data from the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e153","DOI":"10.1161\/CIR.0000000000001052","article-title":"Heart Disease and Stroke Statistics-2022 Update: A Report from the American Heart Association","volume":"145","author":"Tsao","year":"2022","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.thromres.2024.02.010","article-title":"The effects of CYP2C19 genotype polymorphism and clopidogrel resistance on ischemic event occurrence in patients with peripheral arterial disease undergoing revascularization: A prospective cohort study","volume":"236","author":"Zhang","year":"2024","journal-title":"Thromb. 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