Fig. 2

Signaling pathways of RELMα and RELMβ promoting PAH in the lung. RELMα facilitates vascular remodeling through IL-4/IL-4Rα signaling pathway to accelerate PMVECs proliferation, VEGF expression, and MCP-1 production. In PAH, HMGB1, which is produced and released by RELMα-stimulated ECs, leads to induction of autophagy and inhibition of apoptosis and BMPR2 expression in PVSMCs, thus reducing PVSMCs proliferation. ECs-derived HMGB1 also activates RAGE in ECs and PVSMCs to form a positive feedback loop, which contributes to the secretion and release of more HMGB1 and increases the expression of RAGE in these pulmonary vascular cells. RELMα induces robust proliferation of MSCs dependent on PI3K/Akt and ERK1/2 activation. RELMβ triggers PASMCs proliferation and pulmonary artery remodeling, resulting in PAH at least partially through Ca²⁺-dependent PI3K/Akt/mTOR pathway and protein kinase C (PKC)/MAPK pathway. RELMβ leads to PLC-mediated inhibition of KCNK3, thereby promoting PASMCs proliferation during PAH development. RELMβ promotes the proliferation of human PASMCs via the FAK-survivin pathway. In BECs, RELMβ increases cells proliferation through phosphorylation of ERK1/2, PI3K and Akt, and elevates the expression of a range of remodeling mediators, including TGF-β2, EGF, VEGF, and MUC5AC, which contribute to airway remodeling. RELMβ increases the production of TGF-β1, TGF-β2, collagen I, fibronectin, α-SMA, laminin α1, and Hapl1 as well as the proliferation of human lung fibroblasts, which have an important functional role in airway remodeling. TGF-β1 can trigger RELMβ transcription to promote EndMT, proliferation, and migration in human UVECs and human PAECs by activation of SMAD2/3/4