Natriuretic peptide receptor A (NPRA), the signaling receptor for the cardiac
hormone,
atrial natriuretic peptide (
ANP), is expressed abundantly in inflamed/injured tissues and
tumors. NPRA deficiency substantially decreases tissue
inflammation and inhibits
tumor growth. However, the precise mechanism of NPRA function and whether it links
inflammation and
tumorigenesis remains unknown. Since both injury repair and
tumor growth require stem cell recruitment and angiogenesis, we examined the role of NPRA signaling in
tumor angiogenesis as a model of tissue injury repair in this study. In in vitro cultures, aortas from NPRA-KO mice show significantly lower angiogenic response compared to wild-type counterparts. The NPRA antagonist that decreases NPRA expression, inhibits
lipopolysaccharide-induced angiogenesis. The reduction in angiogenesis correlates with decreased expression of
vascular endothelial growth factor and
chemokine (C-X-C motif) receptor 4 (CXCR4) implicating a cell recruitment defect. To test whether NPRA regulates migration of cells to
tumors, mesenchymal stem cells (MSCs) were administered i.v., and the results showed that MSCs fail to migrate to the tumor microenvironment in NPRA-KO mice. However, coimplanting
tumor cells with MSCs increases angiogenesis and
tumorigenesis in NPRA-KO mice, in part by promoting expression of CXCR4 and its
ligand, stromal cell-derived factor 1α. Taken together, these results demonstrate that NPRA signaling regulates stem cell recruitment and angiogenesis leading to
tumor growth. Thus, NPRA signaling provides a key linkage between
inflammation and
tumorigenesis, and NPRA may be a target for
drug development against
cancers and tissue injury repair.