{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T06:54:43Z","timestamp":1770274483377,"version":"3.49.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2014,12,17]]},"abstract":"\n Background<\/jats:title>\n \n Heparanase is the major enzyme involved in degradation of endothelial heparan sulfates, which is associated with impaired endothelial nitric oxide synthesis. However, the effect of heparan sulfate chain length in relation to endothelial function and nitric oxide availability has never been investigated. We studied the effect of heterozygous mutations in heparan sulfate elongation genes\n \n EXT<\/jats:styled-content>\n 1\n <\/jats:italic>\n and\n \n EXT<\/jats:styled-content>\n 2\n <\/jats:italic>\n on endothelial function in vitro as well as in vivo.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Result<\/jats:title>\n \n Flow\u2010mediated dilation, a marker of nitric oxide bioavailability, was studied in\n Ext1<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n and\n Ext2<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice versus controls (n=7 per group), as well as in human subjects with heterozygous loss of function mutations in\n \n EXT<\/jats:styled-content>\n 1\n <\/jats:italic>\n and\n \n EXT<\/jats:styled-content>\n 2\n <\/jats:italic>\n (n=13 hereditary multiple exostoses and n=13 controls). Endothelial function was measured in microvascular endothelial cells under laminar flow with or without si\n RNA<\/jats:styled-content>\n targeting\n \n EXT<\/jats:styled-content>\n 1\n <\/jats:italic>\n or\n \n EXT<\/jats:styled-content>\n 2\n <\/jats:italic>\n . Endothelial glycocalyx and maximal arteriolar dilatation were significantly altered in\n Ext1<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n and\n Ext2<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice compared to wild\u2010type littermates (glycocalyx: wild\u2010type 0.67\u00b10.1\u00a0\u03bcm,\n Ext1<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n 0.28\u00b10.1\u00a0\u03bcm and\n Ext2<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n 0.25\u00b10.1\u00a0\u03bcm,\n P<\/jats:italic>\n <0.01, maximal arteriolar dilation during reperfusion: wild\u2010type 11.3\u00b11.0%),\n Ext1<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n 15.2\u00b11.4% and\n Ext2<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n 13.8\u00b11.6%\n P<\/jats:italic>\n <0.05). In humans, brachial artery flow\u2010mediated dilation was significantly increased in hereditary multiple exostoses patients (hereditary multiple exostoses 8.1\u00b10.8% versus control 5.6\u00b10.7%,\n P<\/jats:italic>\n <0.05). In line, silencing of microvascular endothelial cell\n \n EXT<\/jats:styled-content>\n 1\n <\/jats:italic>\n and\n \n EXT<\/jats:styled-content>\n 2\n <\/jats:italic>\n under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho\u2010endothelial nitric oxide synthesis protein expression.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our data implicate that heparan sulfate elongation genes\n \n EXT<\/jats:styled-content>\n 1\n <\/jats:italic>\n and\n \n EXT<\/jats:styled-content>\n 2\n <\/jats:italic>\n are involved in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.114.001274","type":"journal-article","created":{"date-parts":[[2014,12,3]],"date-time":"2014-12-03T06:12:20Z","timestamp":1417587140000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["Loss of Function in Heparan Sulfate Elongation Genes\n EXT1<\/i>\n and\n EXT 2<\/i>\n Results in Improved Nitric Oxide Bioavailability and Endothelial Function"],"prefix":"10.1161","volume":"3","author":[{"given":"H. L.","family":"Mooij","sequence":"first","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Cabrales","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, UC San Diego, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. J.","family":"Bernelot Moens","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, UC San Diego, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. D.","family":"Udayappan","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. G.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, UC San Diego, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. A. J.","family":"van der Sande","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"de Groot","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Intaglietta","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, UC San Diego, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. J. P.","family":"Kastelein","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. M.","family":"Dallinga\u2010Thie","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. D.","family":"Esko","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, UC San Diego, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E. S.","family":"Stroes","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Nieuwdorp","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, AMC\u2010UvA, Amsterdam, The 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