Fig. 6

Notch and AMPK signaling pathways in PH. a Notch signaling pathway and targeted therapy in PH. BMPR2 mutations in PASMCs increase TNF, reducing BMPR2 and activating Notch2. Hypoxia induces the expression of lncRNA Tug1, which activates Notch1 signaling, thereby promoting the migration of PASMCs. Notch3 activation leads PASMC migration. Additionally, it can cause the release of NICD3, which downregulates p27kip1, further enhancing PASMC proliferation. In PAECs, DLL4 nAbs impair barrier function, and hypoxia activates Notch1 to promote proliferation. Notch signaling contributes to PH, with anti-TNF and Propylthiouracil as potential therapies. PASMC pulmonary artery smooth muscle cell, BMPR2 bone morphogenetic protein receptor type 2, TNF tumor necrosis factor, miR microRNA, PAH pulmonary arterial hypertension, Notch1/2/3 Notch receptors 1/2/3, FOXC1 forkhead box C1, NICD Notch intracellular domain, SKP2 S-phase kinase-associated protein 2, Hes1 hairy and enhancer of split 1, p27kip1 cyclin-dependent kinase inhibitor 1B, PAEC pulmonary artery endothelial cell, DLL4 Delta-like ligand 4, N1-ICD Notch1 intracellular domain, p21 cyclin-dependent kinase inhibitor 1A, Bcl-2 B-cell lymphoma 2, survivin Baculoviral IAP repeat-containing 5, HPAH heritable pulmonary arterial hypertension, lncRNA long non-coding RNA, Tug1 taurine-upregulated gene 1. b AMPK signaling pathway and targeted therapy in PH. In hypoxia-PH, miR-663b is upregulated in macrophages, releasing exosomes that suppress AMPK in PASMCs, driving inflammation, oxidative stress, and proliferation. In IPAH PASMCs, NOX4 activates mTOR, inhibiting AMPK and promoting proliferation. In PAECs, suppressed AMPK in PPHN impairs angiogenesis and mitochondrial function. Metformin upregulate AMPK, mitigating PH progression. AMPK AMP-activated protein kinase, PH pulmonary hypertension, PASMC pulmonary artery smooth muscle cell, PAEC pulmonary artery endothelial cell, miR microRNA, IPAH idiopathic pulmonary arterial hypertension, NOX4 NADPH oxidase 4, mTOR mechanistic target of rapamycin, SIRT1 sirtuin 1, YAP Yes-associated protein, FOXM1 forkhead box M1, Cyclin D cyclin D1, Gal-3 galectin-3, PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, ETC electron transport chain, PPHN persistent pulmonary hypertension of the newborn, ATP adenosine triphosphate, PAH pulmonary arterial hypertension