Emerging Pathogenetic Mechanisms of Pulmonary Arterial Hypertension: Nitric Oxide and More

Pulmonary arterial hypertension (PAH) is a rare but serious clinical condition characterized by a progressive increase of pulmonary arterial pressure and resistance leading to right ventricular and premature death.1) Although PAH clinically includes 9 different subgroups, it has a common final pathology, which is obstructive thickening/hypertrophy in the vascular wall components, mainly affecting distal pulmonary arteries.2) Vascular proliferation and remodeling, in comparison with vasoconstriction or thrombosis, is now recognized as a principal contributor to increased pulmonary resistance.3) The exact processes that initiate the pathological changes seen in PAH are largely unknown. Nonetheless, recent advances in cellular and molecular biology have improved our understanding of some of key mechanisms responsible for pathobiology of PAH. The pathobiology of PAH is multifactorial, and involves various cellular mediators and pathways. Endothelial cells are major regulators of vascular function, and pulmonary arterial endothelial cells (PAEC) have been perceived as the most likely cell type in which dysfunction initiates PAH.4) Endothelial dysfunction leads to reduced production of vasodilators and growth inhibitors such as nitric oxide (NO) and prostacyclin, and increased production of vasoconstrictors and promitogens such as thromboxane A2 and endothelin-1. Vascular NO production is catalyzed by endothelial NO synthase (eNOS) which is expressed constitutively in most endothelial cells. Due to the wide availability and versatility of NO in many vascular beds, its role in PAH has been pursued in many studies. In the present issue of Korean Circulation Journal, Koo et al.5) added to these studies by exploring the expression of NOS in the rat model of pulmonary hypertension induced by monocrotaline (MCT) administration, which is a commonly used technique to simulate PAH in animals. Koo et al.5) reported a significant increase in eNOS expression on day 28, and an increase in matrix metalloproteinase-2 (MMP-2) on day 5 and 28 in the lung tissue of MCT-injected rats, all of which were abrogated by bosentan treatment. Levels of eNOS expression during the development of pulmonary hypertension have been reported at variable levels. Pulmonary eNOS expression was observed as unchanged, decreased or increased in experimental or human PAH.6-8) Nevertheless, there is growing consensus that pulmonary arterial wall in PAH has reduced levels of NO.9) Thus, an inconsistency appears between expression of eNOS and tissue level of NO in the model of PAH. However, recent research has elucidated a number of cellular and molecular processes which might account for the underlying disturbances observed in PAH,10)17) which could reconcile the conflicting data. The discovery of the association of PAH with a mutation of bone morphogenetic protein receptor-2 (BMPR2) has increased knowledge on the pathobiology of PAH. Mutations in the BMPR2 gene have been found in nearly 70% of familial PAH, and up to 25% of idiopathic PAH.11) Bone morphogenetic protein (BMP), a member of the TGF-¥á superfamily, regulates cell growth, differentiation, and apoptosis. Mutation or downregulation of BMPR2 increases susceptibility to apoptosis in endothelial cells, and promotes proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs).12)13) Apart from genetic alteration, ultrastructural changes in the PAH model suggest that another mechanism plays a role. These changEmerging Pathogenetic Mechanisms of Pulmonary Arterial Hypertension: Nitric Oxide and More