{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:34:27Z","timestamp":1791315267593,"version":"4.3.1"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\u03b1-Syn (alpha-synuclein) increases and oligomerization contributes to ischemic brain damage. Nevertheless, the exact mechanisms of ischemia-induced \u03b1-Syn pathology after stroke are understudied. In this exploratory and hypothesis-testing study, we specifically investigated how ischemia-induced \u03b1-Syn pathology impacts vascular inflammation and angiogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Transient focal cerebral ischemia was induced in C57BL\/6J wild-type and C57BL\/6S mice with spontaneous deletion of \u03b1-Syn. In total, 72 mice were randomized to receive sham (12) or ischemia (60), with 1:1 allocation to genotype. Ischemic mice were included if presenting \u22653 intraischemic focal deficits. Experimental end points were 48 hours (acute phase) and 7 days (subacute phase) of reperfusion. Sensorimotor assessment, elevated plus maze, and survival analysis were stroke outcome readouts. Brain samples were collected for quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. In vitro ischemia in brain microvascular endothelial cells was used to investigate the direct effect of extracellular \u03b1-Syn.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      In vivo, cerebral ischemia induced \u03b1-Syn 2.5-fold change gene expression, 2.7- to 3.2-fold-change protein oligomerization with apparent localization around cortical ischemic vessels. Improved subacute functional recovery linked to better survival was observed in C57BL\/6S \u03b1-Syn null (87% to end point) versus C57BL\/6J (45%) ischemic mice. The \u03b1-Syn null mice had reduced expression of\n                      <jats:italic toggle=\"yes\">ICAM-1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">MMP-9<\/jats:italic>\n                      , and vascular permeability factors, associated with less infiltrating leukocytes and juxta-vascular microglia in the acute phase. In the subacute phase, they showed upregulated proangiogenic factors (\n                      <jats:italic toggle=\"yes\">VEGF-A<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">VEGFR-2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Angpt-2<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">IL-6<\/jats:italic>\n                      ) and angiogenic vessels. In vitro, brain microvascular endothelial cells upregulated\n                      <jats:italic toggle=\"yes\">ICAM-1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">IL-6<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">VEGFR-2<\/jats:italic>\n                      expression when exposed to recombinant \u03b1-Syn at the beginning of ischemia and to a larger extent when \u03b1-Syn was preconditioned for 18 hours in hypoxia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings indicate that ischemia-triggered pathological \u03b1-Syn leads to worse outcome in stroke mice by promoting endothelial inflammatory response and immune cell infiltration during the acute phase and by limiting angiogenesis in the subacute phase.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.052265","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T09:00:14Z","timestamp":1758186014000},"page":"3424-3437","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Experimental Ischemic Stroke\u2013Induced Alpha-Synuclein Pathology Enhances Endothelial Inflammatory Response and Impairs Angiogenesis"],"prefix":"10.1161","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0905-2654","authenticated-orcid":true,"given":"Tizibt Ashine","family":"Bogale","sequence":"first","affiliation":[{"name":"Division of Pharmacology (T.A.B., G.F., F.L., S.M., A. Bellucci, M.P.), Department of Molecular and Translational Medicine, University of Brescia, Italy."},{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy (T.A.B., D.M., A.V., S.S., A. Bianchi, S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5101-7222","authenticated-orcid":true,"given":"Domenico","family":"Mercurio","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy (T.A.B., D.M., A.V., S.S., A. Bianchi, S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6917-9278","authenticated-orcid":true,"given":"Alessia","family":"Valente","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy (T.A.B., D.M., A.V., S.S., A. Bianchi, S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Seminara","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy (T.A.B., D.M., A.V., S.S., A. Bianchi, S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0751-3082","authenticated-orcid":true,"given":"Gaia","family":"Faustini","sequence":"additional","affiliation":[{"name":"Division of Pharmacology (T.A.B., G.F., F.L., S.M., A. 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