The primary objective is to investigate the physiological function of a newly identified vascular endothelial cell mitogen (VEGF). We will analyze whether agents known to modulate the bioactivity of FGF also act at the VEGF level. These agents are a diverse group, including growth factors such as TGFbeta or TNFalpha, as well as unrelated molecules, such as heparin, suramin, and protamine, known to affect the angiogenic process and vascular endothelial cells proliferation. The ability of VEGF to control events related to the angiogenic process will be determined. This includes its effect on the chemotactic activity of vascular endothelial cells and its ability to stimulate plasminogen activator and collagenase, while repressing plasminogen inhibitor activity. We will study the expression of VEGF in normal versus tumor cell types. The various normal cell types to be looked at for VEGF expression are vascular endothelial and smooth muscle cells, platelet, monocytic cells, macrophages, and granulosa cells. These cell types are chosen because of their particular relevance to the angiogenic process. If expressed, VEGF could play a role in controlling developmental processes (angiogenesis, vasculogenesis), as well as a pathological one (atherosclerosis). Among the tumor cell types to be analyzed will be those derived from the vascular systems, as well as glioma cells. To study the effect of unregulated VEGF and betaFGF expression on developmental processes, chick embryos will be infected with avian retrovirus carrying the VEGF and betaFGF gene. The tissue specific pattern of viruses expressing the VEGF and betaFGF gene will then be followed as a function of time. This will be correlated with abnormality of development, particularly in the vascular system. We will define the cell surface receptor for VEGF. This is the first step toward cloning of the receptor, as well as a step towards understanding the molecular mechanism of the cells response to this growth factor.
Showing the most recent 10 out of 29 publications
