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CELLULAR AND MOLECULAR

In Vitro Evaluation of the Angiostatic Potential of Drugs Using an Endothelialized Tissue-Engineered Connective Tissue

Laboratoire d'Organogénèse Expérimentale, Hôpital du Saint-Sacrement, Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, Canada

The development of a new pharmacological strategy, the angiostatic therapy, to inhibit solid tumor progression has increased the need of powerful in vitro models to screen the angiostatic potential of new drug candidates. We produced an endothelialized reconstructed connective tissue (ERCT) that promotes the spontaneous formation of a human capillary-like network by coculture of human endothelial cells isolated from umbilical cord or from newborn foreskin, with dermal fibroblasts in a collagen sponge. Three inhibitors of angiogenesis, tamoxifen, ilomastat, and echistatin, were used to assess the efficiency of our ERCT to discriminate, in vitro, an angiostatic potential. The capillary-like structures were characterized by their immunoreactivity to human platelet-endothelial cellular adhesion molecule-1 antibodies and were quantified on histological cross-sections of biopsies taken after 10, 17, 24, and 31 days of culture. A dose-response significant inhibition of the capillary-like formation was detected when increasing concentrations of tamoxifen, ilomastat, or echistatin were added for 1 week to the culture medium of the ERCT. Tamoxifen was found to be angiogenic at 10 µM and to have a cytotoxic effect at 40 µM 1 week after drug removal. Echistatin induced a rapid, slight, and reversible inhibition of capillary-like formation, whereas ilomastat caused a very precocious, strong, and reversible inhibition of angiogenesis. In addition, a 16-h hypoxia promoted the formation of 10 times larger vessels (>300 µm²), compared with normoxic condition. These results suggest that our model could be efficiently used to study the long-term angiostatic potential of drugs in vitro in a very physiological environment.

Address correspondence to: Dr. François A. Auger, Laboratoire d'Organogénèse Expérimentale, Hôpital du Saint-Sacrement, 1050 chemin Sainte-Foy, Québec, QC Canada G1S 4L8. E-mail: francois.auger{at}chg.ulaval.ca

This article has been cited by other articles:

				F. A. Auger, P. D'Orleans-Juste, and L. Germain Adventitia contribution to vascular contraction: Hints provided by tissue-engineered substitutes Cardiovasc Res, September 1, 2007; 75(4): 669 - 678. [Abstract] [Full Text] [PDF]