title: Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension.
abstract: Discussions of the initiation of pulmonary arterial hypertension (PAH) in man and in experimental models have centered around intimal and medial proliferation in medium-sized pulmonary arteries. The histologic events are thought to include disordered proliferation of enlarged, vacuolated endothelial cells, neo-muscularization of the affected blood vessels, and vascular pruning. The discovery of the association of familial and sporadic PAH with mutations in BMPR2 has generated intense interest in cytokine receptor trafficking and function in the endothelial cell and how this might be disrupted to yield an enlarged proliferative cell phenotype. Nevertheless, considerations of the subcellular machinery of membrane trafficking in the endothelial cell and consequences of the disruption of this outward and inward membrane trafficking are largely absent from discussions of the pathobiology of PAH. Long-standing electron microscopy data in the PAH field has demonstrated marked disruptions of intracellular membrane trafficking in human and experimental PAH. Further, a role of the membrane-trafficking regulator Nef in simian HIV-induced PAH in macaques and in HIV-induced PAH in man is now evident. Additionally, monocrotaline and hypoxia are known to disrupt the function of Golgi tethers, SNAREs, SNAPs, and N-ethylmaleimide-sensitive factor ("the Golgi blockade hypothesis"). These results, along with recent reports demonstrating the trapping of PAH-associated human BMPR2 mutants in the Golgi, highlight the implications of disrupted intracellular membrane trafficking in the pathobiology of PAH. The purpose of this review is to present a brief overview of the molecular basis of intracellular trafficking and relate these considerations to the pathobiology of PAH.
authors.affiliation: Basic Sciences Building, Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USA. pravin_sehgal@nymc.edu
authors.forename: Pravin B
authors.initials: PB
authors.lastname: Sehgal
authors.forename: Somshuvra
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D001692:Biological Transport; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D005799:Genes, Dominant; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia; D008854:Microscopy, Electron; D008954:Models, Biological; D009154:Mutation; D011651:Pulmonary Artery / Q000473:pathology*
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II