Figure 1

Summary of molecular mechanisms involved in pulmonary remodeling. In pulmonary artery smooth muscle cells, inhibition of the potassium channels leads to cell depolarization and calcium entry, stimulating excess calcium release from the sarcoplasmic reticulum leading to calcium-calmodulin-regulated cell proliferation. When growth factors (PDGF, VEGF, TGF-β) and mitogens (ET-1) bind to their receptors, various signaling pathways are activated which increase cytosolic calcium levels and activate the MAPK signaling pathway-stimulating transcription factors (c-fos, c-jun, c-myc, and so on) and increase cell proliferation. Prostacyclin’s antagonistic effects act by increasing cAMP concentration, which simultaneously inhibits MAPK signaling and activates the PKA/MLCK growth-suppressive pathway. The vasodilator nitric oxide diffuses into the cell and stimulates cGMP production via guanylyl cyclase that results in MLCK dephosphorylation that inhibits cell growth and relaxes the SMC, leading to vasodilation. Finally, depolarization of the mitochondrial membrane by the mitoK_ATP channels (see mitoK_ATP above) delays apoptosis by inhibiting cytochrome c release and generates hydrogen peroxide (H₂O₂), stimulating transcription factors that drive cell proliferation. Cyto-C, cytochrome c; CaM: calcium-calmodulin complex; S.R, sarcoplasmic reticulum; RyR, ryanodine receptor; PKA, protein kinase A; AC, adenylyl cyclase; GC, guanylyl cyclase; N.O., nitric oxide. Lightning bolt indicates hyperpolarization.