The development of new blood vessels from pre-existing vessels (angiogenesis) is essential for normal wound healing and is often inadequate in poorly healing wounds. On the other hand solid tumor growth and metastases can be facilitated by angiogenesis. Thus understanding how to accelerate or impair angiogenesis has broad clinical relevance. We have been focusing on how endothelial cells coordinately regulate expression of genes for extracellular matrix proteins, matrix degrading proteinases, and cellular adhesion molecules, which are essential in the development of new capillaries. In particular we are investigating the role of Homeobox (Hox) master transcriptional factors that appear to control expression of many of these genes associated with matrix remodeling during angiogenesis. We have identified Hox genes that can either promote angiogenesis, or those that appear to inhibit this process. Specifically we have shown that Hox D3, Hox A3 and Hox B3 all promote angiogenesis and using a novel gene transfer method, we can accelerate closure of problem diabetic wounds as well as poorly healing wounds in aged tissues. Moreover, the expression of pro-angiogenic genes is dysregulated in diabtic and aged tissues and we are exploring how altered mechanical loading of aged skin leads to reduced Hox gene expression. We have also observed that Hox D10 and Hox A5 impair angiogenesis by impairing cell migration and promoting vascular cell differentiation or stability of neovessels respectively. Interestingly, expression of these anti-migratory Hox genes is also lacking in infantile hemangiomas and restoring their expression can stabilize these structures. Additionally we are investigating whether restoring expression of these vascular stabilizing genes will also prevent development of brain arteriovenous malformations. We have now developed tissue-specific inducible transgenic mice to allow controlled and restricted expression of Hox genes specifically in the endothelium which can be used to study the contribution of Hox genes in mediating vascular stability in tumors and in vascular malformations. . We have also begun to examine Hox gene expression during differentiation of embryonic stem cells toward and endothelial lineage. Expression of pro-angiogenic Hox3 genes occurs during the early stages of differentiation whereas maturation of progenitor cells is linked to upregulation of the anti-angiogenic HoxD10 and HoxA5 genes. We are currently developing a variety of means to manipulate Hox gene expression in progenitor cells to improve expansion and grafting of progenitor cells in wounds. In addition, we are exploring the role of the anti-invasive Hox D10 gene in breast epithelial tumors. Restoring expression of HoxD10 in tumorigenic epithelial cells prevents tumor cell growth and invasion and also reduce production of secreted angiogenic factors.