Fig. 8

BMPR2 and TGF-β crosstalk with other signaling pathways in PH. a, b The networks of BMPR2 and other signaling pathways in PH. In PAECs, reduced BMPR2 signaling activates TGF-β, triggering EndMT and inflammation through Smad1/5, Smad2/3, and p38 pathways. Additionally, reduced BMPR2 signaling activates ERK1/2 pathways, promoting anti-apoptosis. In PASMCs, reduced BMPR2 signaling, influenced by ET-1 and HMGB1-induced apoptosis, supports proliferation and survival via the TGF-β/Smad1/5/8, and p38 pathways. Hypoxia and MCT stimulate HIF-1α and NF-κB, reducing BMPR2 expression through miR-130a, which promotes EndMT, inflammation, and apoptosis by suppressing β-catenin pathways in PAECs. In PASMCs, PH-induced TNF downregulates BMPR2 signaling, driving cell proliferation and glycolysis through the activation of BMP6/ALK2 and β-catenin, while suppressing miR-124-3p. c The networks of TGF-β and other signaling pathways in PH. Factors such as TGF-β, PDGF, hypoxia, and the condition of COPD contribute to cell proliferation, inflammation, EndMT, ECM remodeling, fibrosis, and myofibroblast differentiation across various cell types (PAECs, PASMCs, PAFs and RVFs), primarily through the activation of the TGFβR and its interactions with key pathways like PI3K/Akt, MAPKs, HIF-1α, and Wnt/β-catenin. PASMC pulmonary artery smooth muscle cell, BMPR2 bone morphogenetic protein receptor type 2, TGF-β transforming growth factor beta, TGFβR transforming growth factor beta receptor, PAEC pulmonary artery endothelial cell, ET-1 endothelin-1, HMGB1 high-mobility group box 1, Akt protein kinase B, ERK1/2 extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, HIF-1α hypoxia-inducible factor 1-alpha, MAPKs mitogen-activated protein kinases, miR microRNA, ID inhibitor of differentiation, PI3K phosphoinositide 3-kinase, Notch3 Notch receptor 3, PDGF platelet-derived growth factor, ROS reactive oxygen species, Wnt5a/b Wnt family member 5A/B, COPD chronic obstructive pulmonary disease, IPAH idiopathic pulmonary arterial hypertension, ECM extracellular matrix, EndMT endothelial-to-mesenchymal transition, Skp2 S-phase kinase-associated protein 2, Hes1 hairy and enhancer of split 1, p27Kip1 cyclin-dependent kinase inhibitor 1B, N1-ICD Notch1 intracellular domain, p21 cyclin-dependent kinase inhibitor 1A, Bcl-2 B-cell lymphoma 2, survivin Baculoviral IAP repeat-containing 5