Recent identification of TMEM184A as a heparin receptor in vascular cells provides an opportunity to investigate further the mechanism(s) by which the heparin receptor works in vivo. Saturating the heparin receptor decreases vascular smooth muscle cell proliferation and decreases inflammatory responses and angiogenesis in endothelial cells, while decreasing the receptor expression also decreases angiogenesis. The current proposal is designed to expand our knowledge about the heparin receptor and its function in both vascular smooth muscle cells and endothelial cells using a combination of cell culture assays, assays of developmental and regenerative angiogenesis in zebrafish, and employing a null mutant for the heparin receptor currently being developed. Specifically, we will test the hypothesis that the heparin receptor modulates growth factor and adhesion signaling in vascular smooth muscle cells through eNOS activation, examine the hypothesis that mechanotransduction through the endothelial flow mechanosensing complex involves TMEM184A, and test the hypothesis that the heparin receptor collaborates in signaling through the VEGFR2 pathway. Together these studies will provide data to confirm the mechanism(s) by which the heparin receptor is functioning and should yield clues to designing treatments for various vascular diseases that take advance of this modulatory system.
Deaths from cardiovascular disease, complications of angiogenesis, and spending on treatments for individuals suffering from these diseases are major factors in the costs of health care. The drug heparin has been suggested as a treatment that could decrease progression of the disease, but we have a limited understanding of how heparin might work to help slow disease progress. Our recent studies have begun to identify mechanisms and find that the same mechanisms appear to modulate angiogenesis, and the proposed research is designed to increase our understanding of how the drug heparin works at the molecular level to decrease inflammation in blood vessels, and modulate angiogenesis, and should therefore facilitate development of new treatment strategies for vascular diseases.
