{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T14:37:28Z","timestamp":1769524648389,"version":"3.49.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000},"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. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of \u03b1-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGF\u03b1 and its antagonist angiostatin, in Fabry \u03b1-GAL-Tg\/KO mice and determined circulating VEGF\u03b1 and angiostatin serum levels in patients with Fabry\u2019s disease and healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cryopreserved aortic vessels from six \u03b1-GAL-Tg\/KO and six wild-type (WT) mice were obtained and VEGF\u03b1 and angiostatin levels were determined by performing Western blot analysis. VEGF\u03b1 expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGF\u03b1 and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>It was found that there was a significant increase in VEGF\u03b1 protein expression (1.66\u2009\u00b1\u20090.35 vs. 0.62\u2009\u00b1\u20090.16, <jats:italic>p<\/jats:italic>\u2009=\u20090.0009) and a decrease in angiostatin expression (0.024\u2009\u00b1\u20090.007 vs. 0.053\u2009\u00b1\u20090.02, <jats:italic>p<\/jats:italic>\u2009=\u20090.038) in aortic lysates from \u03b1-GAL-Tg\/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGF\u03b1 signal in \u03b1-GAL-Tg\/KO mice, whereas no VEGF\u03b1 signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between \u03b1-GAL-Tg\/KO- and WT mice could be visualized. The serum levels of VEGF\u03b1 were significantly upregulated in patients with Fabry\u2019s disease compared with that in healthy controls (708.5\u2009\u00b1\u2009426.3 vs. 458.5\u2009\u00b1\u2009181.5\u2005pg\/ml, <jats:italic>p<\/jats:italic>\u2009=\u20090.048) and positively associated with albuminuria (<jats:italic>r<\/jats:italic>\u2009=\u20090.82, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001) and elevated NTproBNP (<jats:italic>r<\/jats:italic>\u2009=\u20090.87, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001) and hsTNT values (<jats:italic>r<\/jats:italic>\u2009=\u20090.41, <jats:italic>p<\/jats:italic>\u2009=\u20090.048) in male patients with Fabry\u2019s disease. For angiostatin, no significant difference was found between patients with Fabry\u2019s disease and healthy controls (747.6\u2009\u00b1\u2009390.3 vs. 858.8\u2009\u00b1\u2009599.3\u2005pg\/ml).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In conclusion, an overexpression of VEGF\u03b1 and downregulation of its counter player angiostatin in aortic tissue of \u03b1-GAL-Tg\/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGF\u03b1 serum levels were also observed in patients with Fabry\u2019s disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGF\u03b1, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2024.1355033","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T08:33:56Z","timestamp":1707122036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Overexpression of VEGF\u03b1 as a biomarker of endothelial dysfunction in aortic tissue of \u03b1-GAL-Tg\/KO mice and its upregulation in the serum of patients with Fabry\u2019s disease"],"prefix":"10.3389","volume":"11","author":[{"given":"N.","family":"Lund","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Wieboldt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Muschol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Braun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Huber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Sorriento","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G.","family":"Iaccarino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.","family":"M\u00fcllerleile","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Tahir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G.","family":"Adam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Kirchhof","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Fabritz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Patten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1016\/S0140-6736(08)61589-5","article-title":"Fabry\u2019s 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