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. Dr. Boudreau’s research group has 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 they 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.
The research group has identified Hox genes that can either promote angiogenesis, or those that appear to inhibit this process. Specifically they have shown that Hox D3, Hox A3 and Hox B3 all promote angiogenesis and using a novel gene transfer method, they 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 diabetic and aged tissues and are exploring how altered mechanical loading of aged skin leads to reduced Hox gene expression. They 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, the research group is investigating whether restoring expression of these vascular stabilizing genes will also prevent development of brain arteriovenous malformations. They 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. They 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.
The research group is 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, they 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 reduces production of secreted angiogenic factors.