Figure 2.

Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension. (a) Productive transcriptional signaling from the plasma membrane to the nucleus along the BMP/Smad1/5, TGFβ/Smad2 and IL-6/PY-STAT-3 signaling pathways is membrane associated. IL-6/STAT3 and ERK1/2 signaling is inversely related to loss of caveolar/raft cav-1. (b) Golgi blockade mechanisms in PAH. MCTP and hypoxia lead to a trapping of vesicle tethers, SNAREs and SNAPs in the Golgi of affected pulmonary arterial endothelial cells. This leads to a block in anterograde trafficking of vasorelevant cargo proteins such as cav-1 and eNOS and reduced caveolar NO production. The intracellularly sequestered eNOS produces NO which may potentially S-nitrosylate cysteine-rich proteins like NSF, further inhibiting traffi cking. Golgi-trapped dominant negative BMPR 2 mutants may also potentially block trafficking of cargo proteins to the plasma membrane. (Adapted from ref. 8.)