Growth of new blood vessels, angiogenesis, is an important adaptive mechanism that occurs in skeletal muscle in response to chronic exercise. During angiogenesis, endothelial cells within the blood vessel are stimulated to proliferate then migrate away from the parent vessel into the surrounding extracellular matrix. The regulation of this process is not well understood. The emphasis of my lab?s research is the elucidation of key molecular and biochemical mechanisms that are critical during the initiation and cessation of vascular remodelling events. Proteolysis of basement membrane matrix proteins, which permits subsequent endothelial cell invasion into the surrounding interstitial matrix, is thought to be one of the initial steps in angiogenesis. Matrix metalloproteinases (MMPs) constitute a family of enzymes with specificity for various extracellular matrix proteins, and are known to play key roles in cellular processes involving matrix proteolysis (angiogenesis, tumour cell metastasis, T lymphocyte transmigration, embryo implantation).
Recently, we have characterized transcriptional control elements for 2 specific MMPs (MMP-2 and MT1-MMP) in the context of endothelial cells undergoing angiogenesis. The identification of these transcription factors and their DNA binding domains will now allow us to define upstream signalling events that are necessary for the induction of MMP transcription. Of particular interest is the identification of cell surface receptors that are required to initiate the signalling cascade. Additional experiments using an animal model of angiogenesis are used to clarify the obligatory roles of MMP-2 and MT1-MMP in the angiogenic process as it occurs in an intact organ system. Together, these experiments will shed new light on the regulation of the proteolytic phase of angiogenesis, providing new opportunities for the controlled manipulation of this process.
Han, X., P.J. Boyd, S. Colgan, J.A. Madri and T. L. Haas. Transcriptional upregulation of endothelial cell matrix metalloproteinase-2 in response to extracellular cues involves GATA-2. J. Biol. Chem., In Press, 2003.
Rivilis, I., M. Milkiewicz, P. Boyd, J. Goldstein, M.D. Brown, S. Egginton, F.M. Hansen, O. Hudlicka, T.L. Haas. Differential involvement of MMP-2 and VEGF during muscle stretch- versus shear stress-induced angiogenesis. Am. J. Physiol. 283:H1430-H1438, 2002.
Haas, T.L., M. Milkiewicz, S.J. Davis, A.L. Zhou, S. Egginton, M.D. Brown, J.A. Madri, O. Hudlicka. MMP-2 and MT1-MMP are upregulated and matrix metalloproteinase activity is required for adaptive angiogenesis in rat skeletal muscle. Am. J. Physiol. 2000(279):H1540-H1547.