Vitamin D3 Deficiency Exacerbates Abdominal Aortic Aneurysm Progression Via Complement C3a Activation

Abdominal aortic aneurysm (AAA) is a chronic inflammatory vascular disease characterized by progressive extracellular matrix degradation, vascular smooth muscle cell (VSMC) loss, and immune cell infiltration, ultimately leading to aortic dilation and rupture. Although vitamin 25(OH)D3 deficiency has been associated with cardiovascular inflammation, its mechanistic role in AAA pathogenesis remains poorly defined. Here, we investigated the role of vitamin D{square} mediated signaling to regulate complement pathway activation, particularly the C3a axis, to modulate aneurysm development. Single cell-RNA sequencing analysis of human tissue demonstrated significant differences in Vitamin D and complement pathway-related genes in VSMCs in AAAs compared to control aortic tissue. Using a murine elastase-induced AAA model, we observed that vitamin D3-deficient diet significantly enhances aortic dilation, leukocyte infiltration, proinflammatory cytokine expression and elastin fragmentation, as well as decreases SMC -actin expression compared with vitamin D3-sufficient conditions. Furthermore, vitamin D3 deficiency was accompanied by increased aortic expression of complement component C3a that correlated with vascular inflammation and remodeling during AAA progression. Pharmacological blockade with a C3a receptor antagonist (C3aRA) markedly attenuated AAA formation in two established murine AAA models with concomitant reductions in proinflammatory cytokines and preservation of aortic wall structure. In vitro studies demonstrated that stimulation of VSMCs significantly increased C3a production, which was suppressed by calcitriol (active form of Vitamin D) treatment. These studies suggest that the vitamin D-C3a axis is a critical regulator of vascular inflammation and AAA progression, and postulate that restoring vitamin D{square} sufficiency or targeting C3a signaling may represent a novel therapeutic strategy to limit AAA growth and rupture. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/730431v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18d5d8forg.highwire.dtl.DTLVardef@1f98952org.highwire.dtl.DTLVardef@1a66a95org.highwire.dtl.DTLVardef@9f6439_HPS_FORMAT_FIGEXP M_FIG C_FIG