16.0: Thursday, March 17, 2005

HoxA3 Promotes Endothelial Cell Migration and Angiogenesis

Scott L. Hansen, MD, Nancy J. Boudreau, PhD, and David M. Young, MD.

Introduction: Homeobox (Hox) genes are master transcription factors expressed during angiogenesis and fetal wound healing. We have shown that HoxB3 and HoxD3 promote capillary morphogenesis and endothelial cell (EC) migration. We now report that a paralogous gene, HoxA3, promotes EC migration and angiogenesis in vitro, as well as accelerating deficient wound repair. Methods: Human endothelial cells (HMEC-1) were evaluated on plastic and Matrigel and after fibroblast growth factor stimulation (FGF). HMEC-1 cells were stably transfected with HoxA3. RNA was isolated for Northern blot analysis. Chick chorioallantoic membranes (CAM) were transfected with HoxA3 or control vector. Diabetic mice received either a linear or an excisional wound. The open wounds received either a methylcellulose pellet containing the HoxA3 plasmid or CMVbeta-gal (control). Results: Cultured HMEC-1 cells showed upregulation of HoxA3. In situ hybridization showed increased HoxA3 expression in angiogenic EC's as compared to quiescent EC's. Microarray analysis of HMEC-1 constituitively expressing HoxA3 revealed an increase in MMP-14, uPAR, tenasin and alpha3integrin. We observed a significant increase in angiogenesis in the CAM following infection with HoxA3. HoxA3 significantly accelerates wound healing in the db/db mouse. Conclusion: HoxA3 induces distinct, yet functionally related changes in EC gene expression, and promotes angiogenesis and wound repair.