{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T04:26:35Z","timestamp":1786854395751,"version":"build-2736575974"},"reference-count":100,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Fracture healing depends on coordinated osteogenesis and restoration of the vascular microenvironment. Endothelial cells support skeletal repair through angiogenesis, tissue perfusion and angiocrine signaling that regulates osteoprogenitor recruitment and differentiation. This narrative review examines endothelial dysfunction (ED) as a potential systemic contributor to impaired fracture healing by integrating evidence from vascular biology, experimental models and clinical studies. ED is characterized by reduced nitric oxide (NO) bioavailability, oxidative stress, inflammation and impaired vascular repair. These changes may disrupt angiogenic\u2013osteogenic coupling through altered hypoxia-inducible factor 1-alpha subunit (HIF-1\u03b1)\/vascular endothelial growth factor (VEGF) signaling, endothelial Notch activity, platelet-derived growth factor (PDGF)-mediated vascular remodeling and endothelial progenitor cell (EPC) mobilization. Conditions associated with endothelial dysfunction, including diabetes, aging, chronic kidney disease (CKD), smoking, obesity and chronic inflammatory disease, are also linked to delayed union, nonunion and poorer orthopedic outcomes. Cardiovascular disease and perioperative cardiovascular instability may further impair perfusion and physiological reserve during repair. However, the available evidence is predominantly experimental or observational, and direct causal evidence in fracture patients remains limited. Prospective studies combining standardized endothelial assessments with fracture-healing outcomes are needed to clarify clinical relevance and identify potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms27167278","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:48:36Z","timestamp":1786722516000},"page":"7278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Endothelial Dysfunction in Fracture Healing: Mechanisms and Potential Effects on Skeletal Repair"],"prefix":"10.3390","volume":"27","author":[{"given":"Jakub","family":"Michalczak","sequence":"first","affiliation":[{"name":"Center for Innovative Medical Education, Jagiellonian University Medical College, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Znamierowski","sequence":"additional","affiliation":[{"name":"Center for Innovative Medical Education, Jagiellonian University Medical College, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Bondarowicz","sequence":"additional","affiliation":[{"name":"Center for Innovative Medical Education, Jagiellonian University Medical College, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3489-5063","authenticated-orcid":false,"given":"Wiktoria Ma\u0142gorzata","family":"Zgoda","sequence":"additional","affiliation":[{"name":"Center for Innovative Medical Education, Jagiellonian University Medical College, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9133-4935","authenticated-orcid":false,"given":"Mateusz","family":"Michalczak","sequence":"additional","affiliation":[{"name":"Center for Innovative Medical Education, Jagiellonian University Medical College, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Prigent-Tessier","sequence":"additional","affiliation":[{"name":"CAPS UMR 1093, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Universit\u00e9 Bourgogne Europe, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Basset","sequence":"additional","affiliation":[{"name":"CAPS UMR 1093, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Universit\u00e9 Bourgogne Europe, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0836-1877","authenticated-orcid":false,"given":"Tomasz","family":"Tokarek","sequence":"additional","affiliation":[{"name":"Center for Innovative Medical Education, Jagiellonian University Medical College, 30-688 Krakow, Poland"},{"name":"Center for Invasive Cardiology, Electrotherapy and Angiology, 33-300 Nowy Sacz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.injury.2011.03.031","article-title":"The biology of fracture healing","volume":"42","author":"Marsell","year":"2011","journal-title":"Injury"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.semcdb.2008.07.004","article-title":"Bone remodeling during fracture repair: The cellular picture","volume":"19","author":"Schindeler","year":"2008","journal-title":"Semin. 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