CGRP attenuates pulmonary vascular remodeling by inhibiting the cGAS-STING-NFB pathway in pulmonary arterial hypertension

Background: Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NF kappa B pathway and secretes proinflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and antiinflammatory effects. Methods: The role of the cGAS-STING-NF kappa B signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NF kappa B signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. Results: Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NF kappa B pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NF kappa B pathway through PKA. Conclusion: This study identifies that CGRP attenuates cGAS-STING-NF kappa B axis-mediated vascular remodeling in PAH through PKA.