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

Departments of ¹Cell Biology and Anatomy and ²Medicine, New York Medical College, Valhalla, New York

Submitted 20 December 2006 ; accepted in final form 4 April 2007

ABSTRACT

Histological and electron microscopic studies over the past four decades have highlighted "plump," "enlarged" endothelial, smooth muscle, and fibroblastic cellular elements with increased endoplasmic reticulum, Golgi stacks, and vacuolation in pulmonary arterial lesions in human and in experimental (hypoxia and monocrotaline) pulmonary arterial hypertension. However, 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 intracellular 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 membrane tethers, SNAREs and SNAPs, and to suggest how their dysfunction, 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

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