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While downstream fragments such as C5a contribute to vascular injury, the role of the early anaphylatoxin C3a remains unclear. This study delineates the effects of the C3a:C3a-Receptor-axis on endothelial function, cytoskeletal dynamics, and eGC integrity. Sixty-four first-time STEMI patients and sixty-four age- and sex-matched healthy controls were enrolled. Patients were stratified into quartiles based on serum C3a concentrations, and comparisons were performed between the lowest vs. highest quartiles as well as between all STEMI patients vs. controls. Inflammatory and glycocalyx parameters were assessed via ELISA, AFM nanoindentation, and monocyte adhesion assays. NO bioavailability was measured chemiluminescence-based. C3a-receptor-antagonists (SB290157 and JR14a), C5a-Receptor1-antagonism (PMX53), as well as Rac1-Inhibition (NSC23766) were used to verify pathway specificity and downstream signaling involvement. High C3a levels were associated with marked endothelial injury: eGC height was reduced (\u2212\u00a044%; p\u2009&lt;\u20090.001), cortical stiffness increased (+\u200935%; p\u2009&lt;\u20090.001), and shedding of Syndecan-1 and heparan sulfate was elevated (+\u2009203%, p\u2009&lt;\u20090.001;\u2009+\u2009181%, p\u2009&lt;\u20090.01). NO bioavailability decreased by 34% (p\u2009&lt;\u20090.05). C3a correlated inversely with eGC height (r\u2009=\u2009\u2009\u2212\u20090.736) and positively with Syndecan-1 (r\u2009=\u20090.856). Treatment with recombinant C3a (250 ng\/mL) induced cortical stiffening (+\u200910.8%; p\u2009&lt;\u20090.001), eGC loss (\u2212\u200924.7%; p\u2009&lt;\u20090.001), actin polymerization (+\u200927.9%; p\u2009&lt;\u20090.001), Rac1 activation (p\u2009&lt;\u20090.05), reduced NO (\u2212\u200938%; p\u2009&lt;\u20090.05), and increased monocyte adhesion (+\u200937%), all reversed by both C3a-Receptor-inhibitiors and by Rac1-inhibition. C3a:C3a-Receptor signaling drives Rac1-mediated cytoskeletal stiffening, eGC degradation, NO reduction, and leukocyte adhesion, promoting endothelial dysfunction in STEMI in both macrovascular and microvascular endothelial cells. This pathway represents a potential therapeutic target to mitigate complement-mediated vascular injury in acute myocardial infarction.<\/jats:p>","DOI":"10.1007\/s00395-026-01181-w","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T13:13:13Z","timestamp":1777381993000},"page":"481-502","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activation of the C3a\u2013C3aReceptor-axis is associated with endothelial dysfunction and glycocalyx damage in ST-elevation myocardial infarction"],"prefix":"10.1007","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8440-6267","authenticated-orcid":false,"given":"Carl","family":"Vahldieck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"L\u00f6ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Hamacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5597-5751","authenticated-orcid":false,"given":"Benedikt","family":"Fels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Rudzewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Weil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3831-1440","authenticated-orcid":false,"given":"Kristina","family":"Kusche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"1181_CR1","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1080\/19336918.2019.1568140","volume":"13","author":"Z Al-Rekabi","year":"2019","unstructured":"Al-Rekabi Z, Fura AM, Juhlin I, Yassin A, Popowics TE, Sniadecki NJ (2019) Hyaluronan-CD44 interactions mediate contractility and migration in periodontal ligament cells. 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