Vascular Biology
Angiogenesis is the process of endothelial cell sprouting from preexisting blood vessels. It plays a crucial role during development, wound repair, and in reproduction. It also is essential for growth of metastatic "seeds" into pathologic macroscopic metastases. Recent work from the lab shows that tumor angiogenesis can be discriminated from physiological angiogenesis genetically, by altering the sulfation state of endothelial heparan sulfate proteoglycans. The mechanism appears to involve altered response to growth factors, in particular VEGF. Projects
involve 
studies of tumor growth in animals bearing mutations in genes involved in heparan sulfate assembly and isolation and study of endothelia from genetically altered mice. The application of genetics to this system suggests targets for the development of heparin-based compounds as anti-angiogenesis/anti-metastasis agents.
Another area of interest concerns the function of heparan sulfate proteoglycans in the establishment and maintenance of vascular permeability. VEGF induces vascular leakage, but the function of heparan sulfate proteoglycans in this process remains unclear. Recent studies suggest that wnt signaling participates in the formation of the blood brain barrier by activating b-catenin, which in turns activates expression of tight junction proteins. Since wnt signaling depends on heparan sulfate in several model systems, we are interested in exploring the role of heparan sulfate.
The parenchymal cells of skeletal, cardiac,and adipose tissue produce lipoprotein lipase, a key enzyme in the turnover of triglyceride-rich lipoproteins in the peripheral circulation (see Lipoproteins). The transport of lipoprotein lipase (LPL) from its site of synthesis in the parenchyma to its site of action on the luminal side of the endothelium appears to occur via heparan sulfate proteoglycans. However, this process has not been studied carefully in relevant tissues and the identity of the heparan sulfate proteoglycans remains unknown. The application of various mutants altered in heparan sulfate biosynthesis and core protein expression to this system should provide insights into the mechanism of transport. Data attained from these studies will provide a more physiologic understanding in the transport of LPL and the pathological consequences involved in its disruption.
Relevant Papers
Wang, L., Fuster, M.M., Sriramarao, P., and Esko, J.D. (2005) Endothelial deficiency of heparan sulfate impairs L-selectin and chemokine mediated neutrophil trafficking during inflammatory responses. Nature Immunol. 6:902-910. News & Views: Parish, C.R. (2005) Nature Immunol. 6, 861-862
Bode, L., Salvestrini, C., Park, P.W., Li, J.-P, Esko, J.D., Murch, S., Freeze, H.H. (2007) Heparan sulfate and syndecan-1 are essential in maintaining intestinal epithelial barrier function. J. Clin. Invest. 118:229-238.
Fuster, M.M., Wang, L., Castagnola, J., Sikora, L., Reddi, K., Lee, P.H.A., Radek, K., Gallo, R.L., Sriramarao, P. and Esko, J.D. (2007) Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J. Cell Biol. 177:539-549