Matrix Metalloproteinases in Angiogenesis and Inflammation

Angiogenesis, the formation of new capillaries, is closely linked to inflammation.

We are interested in the molecular and cellular processes that initiate angiogenesis and control the decision between stabilization or regression of new vasculature, and how these processes are linked to the inflammatory infiltrate. Our work focuses on proteases and related molecules involved in matrix remodeling, and has characterized the contribution of membrane-type matrix metalloproteinase 1 (MT1-MMP) to chemokine and nitric oxide-induced angiogenesis and monocyte migration. We are also interested in MT4-MMP, a GPI-anchored MMP of unknown function.

We recently identified a novel, catalysis-independent function for MT1-MMP in macrophage fusion during osteoclast and giant cell formation. The mechanism involves binding of the MT1-MMP cytosolic tail to the adaptor p130Cas, resulting in increased Rac1 membrane targeting and activity. This finding suggests that MT1-MMP regulation and functions are cell-context dependent, and we are currently testing this hypothesis in endothelial cells in the context of angiogenesis.

We are also conducting proteomic analysis of MT1-MMP and MT4-MMP in endothelial cells and leukocytes, and further efforts are directed at defining the molecular networks in which these proteases participate in these cells. We are exploring the functional impact of MT1-MMP and MT4-MMP through studies in cell-based systems and genetically-modified mouse models. We are also interested in characterizing new molecules of potential relevance to vascular integrity and angiogenesis, such as extracellular matrix metalloproteinase inducer (EMMPRIN).

Through these projects, we aim to extend our knowledge of where, when and how MT-MMPs and their regulators modulate endothelial and leukocyte behavior during the establishment and progression of chronic inflammatory disorders.