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From the Department of Oral Medicine, Pathology, and
Oncology*
and the Department of Biologic and
Material Sciences,
University of Michigan
School of Dentistry, Ann Arbor, Michigan
Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and permeability factor that is potently angiogenic in vivo. We report here studies that suggest that VEGF potentiates angiogenesis in vivo and prolongs the survival of human dermal microvascular endothelial cells (HDMECs) in vitro by inducing expression of the anti-apoptotic protein Bcl-2. Growth-factor-enriched and serum-deficient cultures of HDMECs grown on collagen type I gels with VEGF exhibited a 4-fold and a 1.6-fold reduction, respectively, in the proportion of apoptotic cells. Enhanced HDMEC survival was associated with a dose-dependent increase in Bcl-2 expression and a decrease in the expression of the processed forms of the cysteine protease caspase-3. Cultures of HDMECs transduced with and overexpressing Bcl-2 and deprived of growth factors showed enhanced protection from apoptosis and exhibited a twofold increase in cell number and a fourfold increase in the number of capillary-like sprouts. HDMECs overexpressing Bcl-2 when incorporated into polylactic acid sponges and implanted into SCID mice exhibited a sustained fivefold increase in the number of microvessels and a fourfold decrease in the number of apoptotic cells when examined 7 and 14 days later. These results suggest that the angiogenic activity attributed to VEGF may be due in part to its ability to enhance endothelial cell survival by inducing expression of Bcl-2.
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K. Inoue, J. W. Slaton, D. W. Davis, D. J. Hicklin, D. J. McConkey, T. Karashima, R. Radinsky, and C. P. N. Dinney Treatment of Human Metastatic Transitional Cell Carcinoma of the Bladder in a Murine Model with the Anti-Vascular Endothelial Growth Factor Receptor Monoclonal Antibody DC101 and Paclitaxel Clin. Cancer Res., July 1, 2000; 6(7): 2635 - 2643. [Abstract] [Full Text]
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C. J. Bruns, C. C. Solorzano, M. T. Harbison, S. Ozawa, R. Tsan, D. Fan, J. Abbruzzese, P. Traxler, E. Buchdunger, R. Radinsky, et al. Blockade of the Epidermal Growth Factor Receptor Signaling by a Novel Tyrosine Kinase Inhibitor Leads to Apoptosis of Endothelial Cells and Therapy of Human Pancreatic Carcinoma Cancer Res., June 1, 2000; 60(11): 2926 - 2935. [Abstract] [Full Text] [PDF]
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A. BIROCCIO, A. CANDILORO, M. MOTTOLESE, O. SAPORA, A. ALBINI, G. ZUPI, and D. DEL BUFALO Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line FASEB J, April 1, 2000; 14(5): 652 - 660. [Abstract] [Full Text]
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 B. J. BAUM and D. J. MOONEY THE IMPACT OF TISSUE ENGINEERING ON DENTISTRY J Am Dent Assoc, March 1, 2000; 131(3): 309 - 318. [Abstract] [Full Text] [PDF]
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R. S. Kerbel Tumor angiogenesis: past, present and the near future Carcinogenesis, March 1, 2000; 21(3): 505 - 515. [Abstract] [Full Text] [PDF]
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S. R. Wedge, D. J. Ogilvie, M. Dukes, J. Kendrew, J. O. Curwen, L. F. Hennequin, A. P. Thomas, E. S. E. Stokes, B. Curry, G. H. P. Richmond, et al. ZD4190: An Orally Active Inhibitor of Vascular Endothelial Growth Factor Signaling with Broad-Spectrum Antitumor Efficacy Cancer Res., February 1, 2000; 60(4): 970 - 975. [Abstract] [Full Text]
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D. S. O’Connor, J. S. Schechner, C. Adida, M. Mesri, A. L. Rothermel, F. Li, A. K. Nath, J. S. Pober, and D. C. Altieri Control of Apoptosis during Angiogenesis by Survivin Expression in Endothelial Cells Am. J. Pathol., February 1, 2000; 156(2): 393 - 398. [Abstract] [Full Text] [PDF]
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J. Yang, E. Chang, A. M. Cherry, C. D. Bangs, Y. Oei, A. Bodnar, A. Bronstein, C.-P. Chiu, and G. S. Herron Human Endothelial Cell Life Extension by Telomerase Expression J. Biol. Chem., September 10, 1999; 274(37): 26141 - 26148. [Abstract] [Full Text] [PDF]
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J. S. Schechner, A. K. Nath, L. Zheng, M. S. Kluger, C. C. W. Hughes, M. R. Sierra-Honigmann, M. I. Lorber, G. Tellides, M. Kashgarian, A. L. M. Bothwell, et al. In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse PNAS, August 1, 2000; 97(16): 9191 - 9196. [Abstract] [Full Text] [PDF]
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