1. ¹Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan
2. ²Department of Oral Medicine/Pathology/Oncology, School of Dentistry, University of Michigan, Ann Arbor, Michigan
3. ³Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan
4. ⁴Department of Microbiology and Immunology, School of Medicine, University of Michigan, Ann Arbor, Michigan
5. ⁵Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan
6. ⁶Department of Biomedical Engineering, School of Engineering, University of Michigan, Ann Arbor, Michigan

Correspondence: Dr. Peter J. Polverini, University of Minnesota School of Dentistry, 15-209 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota, 55455. E-mail: neovas@tc.umn.edu

Received 20 July 2000.

Abstract

Current model systems used to investigate angiogenesis in vivo rely on the interpretation of results obtained with nonhuman endothelial cells. Recent advances in tissue engineering and molecular biology suggest the possibility of engineering human microvessels in vivo. Here we show that human dermal microvascular endothelial cells (HDMEC) transplanted into severe combined immunodeficient (SCID) mice on biodegradable polymer matrices differentiate into functional human microvessels that anastomose with the mouse vasculature. HDMEC were stably transduced with Flag epitope or alkaline phosphatase to confirm the human origin of the microvessels. Endothelial cells appeared dispersed throughout the sponge 1 day after transplantation, became organized into empty tubular structures by Day 5, and differentiated into functional microvessels within 7 to 10 days. Human microvessels in SCID mice expressed the physiological markers of angiogenesis: CD31, CD34, vascular cellular adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Human endothelial cells became invested by perivascular smooth muscle -actin–expressing mouse cells 21 days after implantation. This model was used previously to demonstrate that overexpression of the antiapoptotic protein Bcl-2 in HDMEC enhances neovascularization, and that apoptotic disruption of tumor microvessels is associated with apoptosis of surrounding tumor cells. The proposed SCID mouse model of human angiogenesis is ideally suited for the study of the physiology of microvessel development, pathologic neovascular responses such as tumor angiogenesis, and for the development and investigation of strategies designed to enhance the neovascularization of engineered human tissues and organs.