Role of TSP-2
My laboratory is also focused on elucidating the mechanism through which the endogenous inhibitor of angiogenesis TSP-2 limits angiogenesis and arteriogenesis.
We are utilizing an in vitro, TSP-2-sensitive, three-dimensional angiogenesis assay and we are currently investigating the effects of TSP-2 on endothelial cells. Our aim is to identify the signaling pathways that mediate the anti-angiogenic effect of TSP2. We have recently shown that TSP2 is critical for the recovery of blood flow in an experimental model of hindlimb ischemia, predominantly through enhanced arteriogenesis in the upper limb and increased angiogenesis in the lower limb.
Finally, we are working on translating our basic findings regarding TSP2 function into a strategy for the generation of matrix-coated synthetic vascular grafts. Based on the assumption that a TSP2-null-derived matrix could confer anti-thrombotic and pro-angiogenic properties to the luminal surface of synthetic vessels, we have pursued several in vitro and in vivo studies in order to provide proof-of-principle for our hypothesis. Specifically, we have found that the TSP 2-null-derived matrix is more permissive for endothelial cell migration and compromised in its ability to induce platelet activation. Furthermore, transplantation of denuded aortic segments from TSP2-null to wild type mice indicates that they are resistant to thrombosis and, unlike transplanted wild type segments, remain patent in the long term.