Perspectives Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

doi:10.1152/ajpheart.01386.2006.—Histological and electron micro-scopic studies over the past four decades have highlighted “plump,” “enlarged ” endothelial, smooth muscle, and fibroblastic cellular ele-ments with increased endoplasmic reticulum, Golgi stacks, and vac-uolation in pulmonary arterial lesions in human and in experimental (hypoxia and monocrotaline) pulmonary arterial hypertension. How-ever, the contribution of disrupted intracellular membrane trafficking in the pathobiology of this disease has received insufficient attention. Recent studies suggest a pathogenetic role of the disruption of intra-cellular trafficking of vasorelevant proteins and cell-surface receptors in the development of this disease. The purpose of this essay is to highlight the molecular regulation of vesicular trafficking by mem-brane tethers, SNAREs and SNAPs, and to suggest how their dys-function, directly and/or indirectly, might contribute to development of pulmonary arterial hypertension in experimental models and in humans, including that due to mutations in bone morphogenetic receptor type 2. intracellular vesicular trafficking; Golgi blockade; N-ethylmaleimide-sensitive factor; tethers; nitric oxide; endothelial nitric oxide synthase; caveolin-1; Nef protein THE PATHOBIOLOGY AND MANAGEMENT of pulmonary arterial hy-pertension (PAH) are receiving focused attention from th