Vericiguat significantly reduced aortic calcification and osteogenic markers in rat and mouse models of vascular calcification by modulating the cGMP-PKG-MMP-10 axis.
Does vericiguat reduce vascular calcification in preclinical models?
Vericiguat attenuates vascular calcification by inhibiting VSMC osteogenic differentiation via the cGMP-PKG-MMP-10 axis in preclinical models, suggesting a potential therapeutic role.
BACKGROUND: Vascular calcification (VC), a pathological process driven by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), markedly increases cardiovascular mortality. Vericiguat, a soluble guanylate cyclase stimulator, has shown vascular protective properties, but its role in modulating VC remains poorly investigated. METHODS: VC models were generated using the nephrectomy method or an adenine diet. Calcification in rat VSMCs and aortic rings was induced by high phosphate. VC was evaluated by Alizarin Red staining, calcium quantification, alkaline phosphatase activity, and imaging. Transcriptomic profiling and viral vector approaches were used to investigate the role of MMP-10 (matrix metalloproteinase 10) in vericiguat-regulated VC. RESULTS: Vericiguat treatment significantly reduced aortic calcification and osteogenic markers of VSMCs both in nephrectomy-induced rats and adenine-induced mice. It also inhibited calcium deposition and the phenotypic switch of VSMCs from a contractile to an osteoblastic state in both aortic ring and VSMC cultures. Transcriptomic profiling identified MMP-10 as a key mediator; MMP-10 was upregulated in VC models, and vericiguat reduced its expression. Overexpression of MMP-10 reversed the protective effects of vericiguat, and lentiviral-mediated MMP-10 knockdown confirmed its procalcific role. Mechanistically, vericiguat increased cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) signaling, including phosphorylated vasodilator-stimulated phosphoprotein and phosphorylated c-Jun (transcription factor Jun), ultimately downregulating MMP-10. CONCLUSIONS: Vericiguat inhibits VSMC osteogenic differentiation and attenuates VC by modulating the cGMP-PKG-MMP-10 axis. These findings support vericiguat as a potential therapeutic candidate for VC.
Hao et al. (Wed,) conducted a other in Vascular calcification. Vericiguat was evaluated on Aortic calcification and osteogenic markers of VSMCs. Vericiguat significantly reduced aortic calcification and osteogenic markers in rat and mouse models of vascular calcification by modulating the cGMP-PKG-MMP-10 axis.