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 HIVinduced 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.Keywords: pulmonary hypertension; endothelium; Golgi organelle; vesicular trafficking ELECTRON MICROSCOPY OF CELLULAR ELEMENTS IN ARTERIAL LESIONS IN PULMONARY HYPERTENSIONThe hallmark plexiform or onionskin lesions in the intra-alveolar pulmonary arteries in idiopathic pulmonary arterial hypertension (PAH) consist of disordered collections of enlarged ("megalocytotic") endothelial cells, fibroblasts, and smooth muscle cell elements which lead to reduced arterial lumen, cycles of thrombosis and recanalization, and eventually to progressive right ventricular hypertrophy and cardiac failure (1-3). Electron micro- CLINICAL RELEVANCEThis review highlights an altogether novel way of thinking about the pathobiology of pulmonary arterial hypertension. We posit that the underlying pathogenesis, irrespective of etiology, is related to a disruption of intracellular trafficking.scopic (EM) data collected over the last three to four decades reveals that these "plump," "enlarged," and "vacuolated" cellular elements contain increased endoplasmic reticulum (ER), Golgi stacks, vacuolation, and Weibel-Palade bodies (these are exocytic vesicles) (4-6). Additional data emphasize the observation of dramatic "tubuloreticular" structures on electron microscopy of pulmonary arterial lesions...

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

“…Mechanistically, this loss of cav-1 from caveolae/rafts results from the trapping of cav-1 in the Golgi organelle (reviewed in Refs. 42,43) from where this trapped cav-1 can aberrantly traffic to other cytoplasmic compartments. Finally, that scaffolding domain mutants of cav-1 were equally effective in inhibiting transcriptional IL-6/STAT3 signaling compared with WT cav-1 (Fig.…”

“…caveolin-1; signaling endosome; monocrotaline PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by the reduction of the lumen of medium-sized pulmonary arteries by proliferating, enlarged, vacuolated, and apoptosis-resistant ("megalocytotic") pulmonary arterial endothelial (PAEC) and smooth muscle (PASMC) cells (42,43). We (24, 26 -28, 41-43, 47) recently proposed that dysfunction of vesicle tethers, soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs), and SNAP receptors (SNAREs), leading to disruptions of intracellular trafficking from the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions might represent a key subcellular mechanism leading to the changes observed in endothelial and vascular smooth muscle cells in PAH.…”

“…However, considerations of centripetal signaling from the plasma membrane to the cell interior in the pulmonary hypertension literature have largely represented transcytoplasmic transit of activated signaling molecules as taking place exclusively as a soluble cytoplasmic process (reviewed in Refs. 42,43).…”

Pulmonary Hypertension Associated With HIV Infection

“…Besides the infl ammatory aspect of HRPAH, Sehgal and Mukhopadhyay 25 presented an alternative view that suggests that disrupted subcellular membrane traffi cking in endothelial cells and smooth muscle cells is critical in the pathobiologic aspect of PAH. Observations of endothelial cells in plexiform lesions by electron microscopy revealed plump cells with enlarged endoplasmic reticulum, Golgi stacks, and vacuolation, 26 suggesting defects in intracellular traffi cking.…”

Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging

“…Neointima development, thrombotic obliteration of arterial lumen, and development of plexiform lesions, reminiscent of human PAH, have also been reported with MCT when combined with partial pneumonectomy (44, 65 and citations therein). Additionally, perivascular/adventitial infiltrative cells and their cytokine contributions (such as IL-6) and transcription factors activated by such cytokines (STAT3 and NF-B) have been posited as contributory factors in the development of disease in this model (2,14,15,30,41,64).Over the last two decades bovine PAECs and PASMCs in culture exposed to MCTP have been used as experimental models to investigate some of the cellular, subcellular, and biochemical changes elicited by MCTP (18,25,26,30,[38][39][40][41][42]48,49,[53][54][55]57,61,66). A single exposure of confluent bovine PAEC cultures to MCTP for as short a time as 2 min leads to apoptosis of a small subset of cells with the development of marked megalocytosis of cells in the surviving, but still confluent, cell sheet 18 -24 h later (18,38,48,49,68, 73).…”