Circulation Research. 2003;93:1074-1081
Published online before print October 23, 2003, doi: 10.1161/01.RES.0000102937.50486.1B
Published online before print October 23, 2003, doi: 10.1161/01.RES.0000102937.50486.1B
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Cell Type–Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1
From the Program in Vascular Cell Engineering, Institute for Cell Engineering and the McKusick-Nathans Institute of Genetic Medicine (B.D.K., K.H., Z.C., S.B.-D., A.R., Z.Y., G.L.S.) and the Departments of Ophthalmology and Neuroscience (S.F.H., Y.O., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Gregg L. Semenza, MD, PhD, Johns Hopkins University School of Medicine, 600 N Wolfe St, CMSC-1004, Baltimore, MD 21287-3914. E-mail gsemenza{at}jhmi.edu
Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1
, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1–null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1 is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.
Key Words: angiogenesis • gene therapy • hypoxia
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