Adventitial fibroblast-derived NAMPT is associated with vascular remodeling in erythropoietin-induced abdominal...

Abdominal aortic aneurysm (AAA) remains a life-threatening condition with limited pharmacological interventions. While erythropoietin (EPO) has been implicated in AAA pathogenesis, its cell-type-specific effects on nicotinamide phosphoribosyltransferase (NAMPT)-mediated vascular remodeling remain unexplored. This study demonstrates that EPO administration in mice significantly induces AAA formation, characterized by aortic dilation, straightening of elastic laminae, and adventitial thickening. Through integrated in vivo and in vitro analyses, we identified that EPO differentially regulates NAMPT expression across vascular cell types: downregulating it in endothelial cells while robustly upregulating it in adventitial fibroblasts and infiltrating macrophages. Notably, EPO promoted proliferation of adventitial fibroblasts but suppressed endothelial cell growth. Mechanistically, the vascular adventitia emerged as the primary locus of NAMPT-driven pathology, where fibroblast-derived NAMPT creates a pro-inflammatory and pro-remodeling niche. These findings reveal a previously unrecognized role of adventitial fibroblasts in EPO-induced AAA through NAMPT dysregulation, suggesting novel therapeutic targets for AAA treatment. The study shifts therapeutic focus toward the adventitia as a key regulator of AAA progression.