{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:19:55Z","timestamp":1790734795254,"version":"4.1.0"},"reference-count":77,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T00:00:00Z","timestamp":1672185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Office of the Ministry of Higher Education, Science, Research and Innovation","award":["NIH R01EY018420"],"award-info":[{"award-number":["NIH R01EY018420"]}]},{"name":"Thailand Science Research and Innovation through the Kasetsart University Reinventing Program 2021","award":["NIH R01EY018420"],"award-info":[{"award-number":["NIH R01EY018420"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen peroxide (H2O2) formation to compensate for NO deficiency. This hypothesis was tested in coronary arterioles isolated from pigs with 2-week diabetes after streptozocin injection. The NO-mediated vasodilation induced by flow and VEGF was abolished by NOS inhibitor L-NAME and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin but was not affected by arginase inhibitor N\u03c9-hydroxy-nor-L-arginine (nor-NOHA) or H2O2 scavenger catalase in control pigs. With diabetes, this vasodilation was partially blunted, and the remaining vasodilation was abolished by catalase and wortmannin. Administration of L-arginine or nor-NOHA restored flow-induced vasodilation in an L-NAME sensitive manner. Diabetes did not alter vascular superoxide dismutase 1, catalase, and glutathione peroxidase mRNA levels. This study demonstrates that endothelium-dependent NO-mediated coronary arteriolar dilation is partially compromised in early type 1 diabetes by reducing eNOS substrate L-arginine via arginase activation. It appears that upregulated arginase contributes to endothelial NO deficiency in early diabetes, but production of H2O2 during PI3K-linked eNOS uncoupling likely compensates for and masks this disturbance.<\/jats:p>","DOI":"10.3390\/ijms24010489","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T05:42:48Z","timestamp":1672206168000},"page":"489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["H2O2 Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0815-0743","authenticated-orcid":false,"given":"Naris","family":"Thengchaisri","sequence":"first","affiliation":[{"name":"Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA"},{"name":"Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4912-6910","authenticated-orcid":false,"given":"Lih","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis W.","family":"Hein","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1007\/s00259-002-0977-0","article-title":"Dysregulation of coronary microvascular reactivity in asymptomatic patients with type 2 diabetes mellitus","volume":"29","author":"Momose","year":"2002","journal-title":"Eur. 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