HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair

Abstract

Wound repair requires both the recruitment and coordination of numerous cell types including inflammatory cells, fibroblasts, endothelial and epithelial cells. Each cell type has a distinct set of cell behavior such as formation of granulation tissue and basement membrane, migration, proliferation and redifferentiation. These processes are dependent on cell-cell and cell-ECM signaling, intracellular signal transduction cascades, and ultimately, changes in gene transcription. We have investigated the role of the transcription factor HOXA3 in wound repair and angiogenesis. Here we show that HOXA3 increases endothelial cell migration, induces angiogenesis in vivo, and leads to increased expression of the matrix metalloproteinase-14 (MMP-14) and urokinase-type plasminogen activator receptor (uPAR) genes in endothelial cells in culture and in vivo in response to injury. We find that HOXA3 gene expression is upregulated during wound healing in angiogenic endothelial cells and keratinocytes, and that HOXA3 is not induced in genetically diabetic mice that have impaired angiogenesis and wound repair. We demonstrate that gene transfer of HOXA3 into diabetic mouse wounds leads to dramatic improvements in both angiogenesis and wound closure. In addition, we show that HOXA3 promotes migration of endothelial cells and keratinocytes in a uPAR-dependent manner. Together these findings illustrate how the morphoregulatory protein, HOXA3 can facilitate tissue remodeling via coordinated changes in both epithelial and endothelial cell gene expression and behavior in adult tissues during wound repair.