The role of neuropilin 2 in physiological and pathological angiogenesis
Levonyak, Nicholas S.
MetadataShow full item record
Neuropilin 2 (NRP2) is a transmembrane receptor protein that was first discovered on neurons and then endothelial cells. On endothelial cells, it serves as co-receptor with the vascular endothelial growth factor receptor (VEGFR) to bind VEGF and induce a pro-(lymph)angiogenic intracellular signal. In addition to VEGF, NRP2 is also a receptor for semaphorin 3F (SEMA3F), which upon binding to NRP2 and Plexin A1 induces a strong anti-angiogenic signal. It is our hypothesis that SEMA3F could be a potentially effective treatment for metastatic cancers. A greater understanding of the regulation and expression of its receptor, NRP2, is needed. While NRP2 has been most robustly studied for its role in the vasculature, recent studies have shown that it is expressed on other cell types as well such as dendritic cells, T-cells, and visceral smooth muscle cells. In this study, we used western blot and immunohistochemistry to explore various different organs and cell types in an attempt to locate other novel locations of NRP2 expression. In particular, we found several new tissues that express NRP2 including the uterus and adipose tissue. Interestingly, NRP2 is expressed much more strongly in brown adipose tissue than white adipose tissue. In addition, we found that expression of NRP2 in adult organs is weaker than during development but is apparent, particularly on lung vascular EC and the intestinal lymphatic lacteal. In addition, we used several in vivo angiogenesis assays in order to help understand how NRP2 is regulated in the mature vasculature. We found that in the cutaneous wound healing assay, Nrp2 knockout mice healed at the same rate as their wild-type and heterozygous littermates. However, when delayed type hypersensitivity reactions were induced in these mice, the Nrp2 knockouts demonstrated persistent swelling over a longer period of time in comparison to littermates. We also examined how the loss of NRP2 affected pathological angiogenesis by orthotopically injecting a murine syngeneic pancreatic adenocarcinoma cell line (Panc0H7) into the Nrp2 knockout mice. These mice displayed smaller tumors, less grossly apparent metastases, and less ascites. Taken together, these data suggest that NRP2 is important in physiological and pathological angiogenesis. Anti-NRP2 or SEMA3F strategies may represent promising anti-metastatic therapies.
Thesis (M.A.)--Boston University