Abstract 4366549: FNDC1 is Implicated in Small and Large-vessel Arterial Disease and Induces Vascular Calcification via PI3K/AKT Signaling and the NAD Salvage Pathway

Abstract

Introduction: Vascular calcification is a major contributor to cardiovascular morbidity and mortality, yet the molecular mechanisms of calcification remain poorly defined. Research Question: Here, we aimed to identify novel differentially expressed genes (DEGs) and altered signaling pathways associated with small and large arterial calcification, as modeled by calciphylaxis and coronary artery disease. Methods/Results: Transcriptomic profiling of human calciphylaxis lesions revealed 783 DEGs enriched in pathways related to mineralization, inflammation, and thrombosis, with fibronectin type III domain containing 1 ( FNDC1 ) among the most significantly upregulated (FDR-adjusted p-value ≤ 1.2 x10 -7 ) ( Fig. 1A ). FNDC1 protein expression was also significantly upregulated on immunofluorescent staining of dermal arterioles in calciphylaxis compared to chronic kidney disease-matched controls ( Fig. 1B, left panel ). Similarly, among the top upregulated DEGs in calciphylaxis that were validated at the protein level on immunofluorescent staining, FNDC1 was most significantly upregulated in atherosclerotic coronaries at the transcriptomic (FDR-adjusted p-value = 5.87 x 10 -5 ) and protein level (p = 0.0016) ( Fig. 1B, right panel ). In human vascular smooth muscle cells (VSMCs), FNDC1 promoted osteogenic phenotype switch, proliferation, and migration via PI3K/AKT signaling and upregulated nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD salvage pathway. In murine models, genetic deletion of Fndc1 ( Fig. 2A ) or pharmacologic NAMPT inhibition ( Fig. 2B ) attenuated arterial calcification and improved survival. Clinically, circulating FNDC1 levels were elevated in patients with calciphylaxis and coronary artery disease, and independently predicted coronary risk in over 43,000 UK Biobank participants. Conclusions: These findings position FNDC1 as a central regulator of vascular calcification and highlight the FNDC1–NAMPT axis as a previously unrecognized mechanistic link between vascular signaling and metabolic reprogramming and a tractable target for therapeutic intervention.