Natriuretic Peptide Receptor A Signaling Regulates Stem Cell Recruitment and Angiogenesis: A Model to Study Linkage Between Inflammation and Tumorigenesis

Abstract

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 or 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, inhibit lipopolysaccharide-induced angiogenesis. The reduction in angiogenesis correlates with decreased expression of vascular endothelial growth factor (VEGF) 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, co-implanting tumor cells with MSCs, increases angiogenesis and tumorigenesis in NPRA-KO mice, in part by promoting expression of CXCR4 and its ligand, stromal-derived factor 1α (SDF1α). 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.

Systemic inflammatory response syndrome following burns is mediated by brain natriuretic peptide/natriuretic peptide A receptor‐induced shock factor 1 signaling pathway

“…NPRA is a transmembrane receptor with guanylate cyclase (GC) activity that can synthesize cGMP, which mediates most of the biological effects of BNP such as diuresis, natriuresis, vasodilation, blood pressure reduction, regulation of body fluid volume, and maintenance of electrolyte balance . Recently, NPRA signalling was reported to have a significant role in inflammation‐induced angiogenesis as assayed by endothelial sprouting . In addition, atrial natriuretic peptide/NPRA signalling was shown to induce a predominantly Th2‐type response to activate pathological processes during acute allergic asthma .…”

Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

“…VEGF, EGF). Furthermore, secretion of angiogenic factors in injured tissue could be due to the activation of HIFs [Mallela et al, 2013]. MSCs can also recruit the other MSCs or progenitor cells towards the injury/defect site via paracrine effects [Shao et al, 2015].…”

The multifaceted role of natriuretic peptides in metabolic syndrome

“…The NPR-A has been reported to be expressed in various types of cancer, such as lung cancer, ovarian cancer, gastric cancer and prostate cancer [117–119]. Another study shows the involvement of NPR-A in lung cancer-induced vascular endothelial growth factor (VEGF) expression and angiogenesis [118].…”