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(Circulation. 2001;103:1887.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Increased Vascular Endothelial Growth Factor 165 Binding to Kinase Insert Domain–Containing Receptor After Infection of Human Endothelial Cells by Recombinant Adenovirus Encoding the Vegf₁₆₅ Gene

Anat Weisz, PhD; Belly Koren, MSc; Tzafra Cohen, PhD; Gera Neufeld, PhD; Tamar Kleinberger, PhD; Basil S. Lewis, MD, FRCP; Moshe Y. Flugelman, MD

From the Laboratory of Molecular and Cellular Cardiology, Department of Cardiology, Lady Davis Carmel Medical Center (A.W., B.K., B.S.L., M.Y.F.); the Unit of Molecular Microbiology (T.K.), Bruce Rappaport School of Medicine; and the Faculty of Biology (T.C., G.N.), Technion-IIT, Haifa, Israel.

Correspondence to Moshe Y. Flugelman, MD, Department of Cardiology, Lady Davis Carmel Medical Center, 7 Michal St, Haifa, Israel 34632. E-mail myf{at}tx.technion.ac.il

Background—The angiogenic effect of vascular endothelial growth factor (VEGF₁₆₅) is mediated mainly through the high-affinity tyrosine kinase receptor VEGF-R2 (KDR/flk-1). This study examined the effects of VEGF overexpression by primary human endothelial cells (ECs), which do not express VEGF under physiological conditions, on cell proliferation, VEGF binding to the kinase insert domain–containing receptor (KDR), and KDR expression.

Methods and Results—Human primary ECs and SMCs were infected by recombinant adenoviral vector encoding VEGF₁₆₅ (rAdVEGF). Proliferation rate, bromodeoxyuridine incorporation, ¹²⁵I-labeled VEGF₁₆₅ binding to the KDR receptor, and KDR expression were tested in the infected cells and in cells supplemented with VEGF protein. Enhanced proliferation and a significant increase in ¹²⁵I-VEGF₁₆₅ binding to the KDR receptor were induced by rAdVEGF infection of ECs (autocrine effect) as well as by addition of recombinant VEGF₁₆₅ to noninfected cells. Infection of ECs by rAdVEGF led to posttranscriptional upregulation of the KDR receptor, whereas KDR mRNA expression levels remained unchanged. Similar effects were observed with supplemented recombinant VEGF₁₆₅ to noninfected ECs; nevertheless, this phenomenon occurred only with high VEGF₁₆₅ concentrations (10 ng/mL).

Conclusions—The effect of VEGF₁₆₅ on proliferation and upregulation of KDR receptor expression demonstrated an autocrine phenomenon of EC sensitization. The fact that high concentrations of VEGF may be achieved in vivo by local continuous overexpression of VEGF₁₆₅ by gene transfer emphasizes the potential advantage of gene transfer over protein supplementation for therapeutic angiogenesis.

Key Words: genes • cells • viruses

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