Angiogenesis is the formation of new blood vessels from preexisting ones. In adults, angiogenesis is associated with events such as wound healing, tissue ischemia, vessel occlusion, and also with pathological processes such during tumor growth and metastasis. Notch signaling is a critical regulator of angiogenesis and interacts with several other pathways, including that of vascular endothelial growth factor (VEGF). The overall objective of this proposal is to further define the Notch signaling pathway in angiogenesis and the role that Notch target genes, specifically VEGF receptor-1 (VEGFR-1), play in the survival, sprouting, and proliferation of endothelial cells in response to angiogenic stimuli. In addition, these studies may define a possible role for Notch signaling in VEGFR1 + bone marrow-derived monocytes and their contribution to neovascularization. In vitro assays for sprouting, proliferation, survival, and cord formation using human umbilical vein endothelial cells (HUVECs) will be performed to investigate the contexts in which Notch signaling is dependent on VEGFR-1. Monocytes from bone marrow and peripheral blood will be harvested from mice and used to investigate the connection between Notch signaling and VEGFR-1 in these cells using in vitro expression analysis and functional assays. Further experiments will assess changes in Notch and VEGFR-1 signaling in monocytes as a result of bone marrow mobilization using angiogenic stimuli such as GM-CSF and VEGF-A. These studies will characterize Notch function in vascular homeostasis and may suggest a novel role for Notch in recruitment and function of bone marrow cells at angiogenic sites. The long-term objective of this project is to determine the role of Notch-mediated regulation of VEGFR-1 in pathological processes such as tumor angiogenesis and to identify potential therapeutic targets. The relevance of this research is profound. Not only will it provide fundamental knowledge about a signaling pathway with widespread and significant functions, but it may also lead to insight into the pathogenesis of leading causes of death in this country. Given the abundance of medical disorders and diseases that are the result of vascular malformation or inappropriate blood vessel development, understanding the role of the Notch pathway in these processes is of tremendous importance to public health. Particularly as it is related in tumor growth and metastasis, studies of the mechanism of Notch signaling has far-reaching implications in one of the most prevalent and fatal diseases in our nation. These studies may directly influence the diagnostic strategies and therapeutic approaches for various diseases in which Notch signaling is involved and will constitute a foundation for further research that can directly translate from bench to bedside. ? ? ?
| Outtz, Hasina H; Tattersall, Ian W; Kofler, Natalie M et al. (2011) Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118:3436-9 |
| Kofler, Natalie M; Shawber, Carrie J; Kangsamaksin, Thaned et al. (2011) Notch signaling in developmental and tumor angiogenesis. Genes Cancer 2:1106-16 |
| Outtz, Hasina Hamilton; Wu, June K; Wang, Xing et al. (2010) Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185:4363-73 |
