{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T12:23:56Z","timestamp":1783686236481,"version":"3.55.0"},"reference-count":46,"publisher":"American Diabetes Association","issue":"12","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,12,1]]},"abstract":"<jats:p>OBJECTIVE\u2014 Diabetic impaired angiogenesis is associated with impairment of hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1\u03b1 stabilization and vascular maturation in db\/db mice.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014\u2008db\/db mice were systemically administrated adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1\u03b1, vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), Akt, and HIF-1\u03b1\u2013prolyl-4-hydroxylase-2 (PHD)2 expression were measured. Vasculature maturation, capillary and arteriole densities, and cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium.<\/jats:p>\n               <jats:p>RESULTS\u2014 Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db\/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1\u03b1 stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db\/db mice compared with wild-type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1\u03b1 signaling.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014 Normalization of immature vasculature by Ang-1 gene therapy may represent a novel therapeutic strategy for treatment of the diabetes-associated impairment of myocardial angiogenesis.<\/jats:p>","DOI":"10.2337\/db08-0503","type":"journal-article","created":{"date-parts":[[2008,10,4]],"date-time":"2008-10-04T00:54:48Z","timestamp":1223081688000},"page":"3335-3343","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":74,"title":["Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1\u03b1 (HIF-1\u03b1)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1\u03b1 Expression, and Normalizes Immature Vasculature in <i>db<\/i>\/<i>db<\/i> Mice"],"prefix":"10.2337","volume":"57","author":[{"given":"Jian-Xiong","family":"Chen","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Stinnett","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031207452864800_R1","doi-asserted-by":"crossref","unstructured":"Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ: Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. 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