© 1995 American Heart Association, Inc.
Articles |
VEGF165 Expressed by a Replication-Deficient Recombinant Adenovirus Vector Induces Angiogenesis In Vivo
From the Pulmonary Branch (J.M., H.M., B.B., R.G.C., M.C.C.), National Heart, Lung, and Blood Institute, the Surgical Neurology Branch (M.J.M., M.B., N.A.E.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md; the Laboratory of Biological Chemistry (R.P., A.P.), National Institute on Aging, National Institutes of Health, Baltimore, Md; the Division of Pulmonary and Critical Care Medicine (B.B., R.G.C.), The New York Hospital–Cornell University Medical Center, New York, NY; the Laboratorio di Patologia Vascolare (J.M.), Istituto Dermopatico dell'Immacolata, Roma, Italy; and the Gene Therapy Unit (M.C.C.), Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md.
Correspondence to Maurizio C. Capogrossi, MD, Gene Therapy Unit, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 4940 Eastern Ave, Baltimore, MD 21224.
Abstract To evaluate the concept that localized delivery of angiogenic factors via virus-mediated gene transfer may be useful in the treatment of ischemic disorders, the replication-deficient adenovirus (Ad) vector AdCMV.VEGF165 (where CMV is cytomegalovirus and VEGF is vascular endothelial growth factor) containing the cDNA for human VEGF165, a secreted endothelial cell–specific angiogenic growth factor, was constructed. Human umbilical vein endothelial cells (HUVECs) and rat aorta smooth muscle cells (RASMCs) infected with AdCMV.VEGF165 (5 and 20 plaque-forming units [pfu] per cell) demonstrated VEGF mRNA expression and protein secretion into the supernatant. Furthermore, the conditioned medium from these cells enhanced vascular permeability in vivo. In contrast, neither VEGF mRNA nor secreted protein was found in uninfected HUVECs or RASMCs or in cells infected with the control vector AdCMV.ßgal (where ßgal is ß-galactosidase). Assessment of starved HUVECs at 14 days demonstrated sixfold more cells for AdCMV.VEGF165-infected HUVECs (20 pfu per cell) than for either infected or uninfected control cells. RASMC proliferation was unaffected by infection with AdCMV.VEGF165. When plated in 2% serum on dishes precoated with reconstituted basement membrane (Matrigel), HUVECs infected with AdCMV.VEGF165 (20 pfu per cell) differentiated into capillary-like structures. Under similar conditions, both uninfected HUVECs and HUVECs infected with AdCMV.ßgal did not differentiate. To evaluate the ability of AdCMV.VEGF165 to function in vivo, either AdCMV. VEGF165 or AdCMV.ßgal (2x1010 pfu) was resuspended in 0.5 mL Matrigel and injected subcutaneously into mice. Immunohistochemical staining demonstrated VEGF in the tissues surrounding the Matrigel plugs containing AdCMV.VEGF165 up to 3 weeks after injection, whereas no VEGF was found in the control plugs with AdCMV.ßgal. Two weeks after injection, there was histological evidence of neovascularization in the tissues surrounding the Matrigel containing AdCMV.VEGF165, whereas no significant angiogenesis was observed in response to AdCMV.ßgal. Furthermore, the Matrigel plugs with AdCMV.VEGF165 demonstrated hemoglobin content fourfold higher than the plugs with AdCMV.ßgal. Together, these in vitro and in vivo studies are consistent with the concept that Ad vectors may provide a useful strategy for efficient local delivery of VEGF165 in the treatment of ischemic diseases.
Key Words: angiogenesis • endothelium • gene therapy • VEGF • vascular permeability factor
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