Molecular pathogenesis of pulmonary arterial hypertension

Abstract

Pathological features of PAHPulmonary arterial hypertension (PAH) is diagnosed by an elevation in mean pulmonary arterial (PA) pressure above 25 mmHg at rest or 30 mmHg with exercise. Patients usually present with much higher levels of PA pressure, but only vague and insidious symptoms of increasing fatigue and dyspnea; some patients are diagnosed only after syncopal episodes, which can reflect suprasystemic levels of PA pressure and low cardiac output. The causes of PAH were reclassified according to a consensus at the Fourth World While this review focuses on pulmonary hypertension category 1 (i.e., PAH), pathophysiologic insights can also be gained from understanding other causes of pulmonary hypertension. Hence, experimental studies in hypoxic animals are also discussed.In neonates and in infants, PAH likely results from failure of the neonatal pulmonary vasculature to dilate at birth, and pathological changes in the blood vessels are evident in the first few days of life. Most prominent is abnormal muscularization of distal PAs at the alveolar duct and wall levels and a striking reduction in their number. In older infants and adults, there is also progressive intimal hyperplasia leading to occlusive changes in the PAs and plexiform lesions (Figure 1 and see below).PA EC alterations in the clinical (2) and experimental (3) setting precede muscularization of distal PAs. In PA ECs from patients with idiopathic PAH (IPAH), an increase in Tie2 receptor expression in ECs releases serotonin, mediating SMC proliferation (4). Dysfunctional ECs can either release factors that stimulate SMC proliferation, such as FGF-2 (5), or fail to produce agents that normally suppress proliferation of SMCs in response to growth factors, such as apelin (encoded by Apln) (6).Muscularization of distal, normally nonmuscular, PAs at the alveolar duct and wall level is associated with differentiation of pericytes into SMCs that subsequently proliferate. The progressive thickening of the wall of more proximal intraacinar and preacinar muscular arteries and the obliteration associated with neointimal formation are attributed to increased proliferation and migration of cells considered to be SMCs because they are α-SMA positive (7). The origin of these cells is unclear, and the mechanism of their dysregulation is the subject of intense study. They may represent a specialized subpopulation of SMCs; they may originate as stem cells (8) or fibrocytes (9) or transform from ECs (10, 11). The loss of distal PAs could be caused by alterations in ECs and/or pericytes resulting in apoptosis (12).Later in disease, there is dysregulated EC proliferation, producing aberrant channels in the otherwise obliterated lumen of the vessel and in the adventitia (i.e., the plexiform lesion). These channels may reflect clonal expansion of apoptosis-resistant ECs (13), or they may be derived from circulating endothelial progenitor cells (EPCs) that accumulate at sites of endothelial denudation or injury and expand locally (14). PA ECs from patients with IPAH prod...

Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

“…These vascular abnormalities cause narrowing and even obliteration of the vessel lumen and contribute to the progressive increase in pulmonary vascular resistance that can lead to right ventricular failure (reviewed in Ref. 1). Only a few murine or rodent models recapitulate this pathological feature, eg, mice exposed to ovalbumin or aspergillus 2 or to schistosomiasis, 3 rats treated with the vascular endothelial receptor blocker Sugen 5416, exposed to chronic hypoxia and recovered in room air, 4 mice that overexpress IL-6 and are subjected to chronic hypoxia, 5 or mice that overexpress S100A4.…”

Cellular microparticles in the pathogenesis of pulmonary hypertension

“…The dysfunctional endothelium displays, to varying degrees, an imbalanced production of several mediators (vasoconstrictors versus vasodilators; activators versus inhibitors of smooth muscle cell growth; pro-inflammatory versus anti-inflammatory signals; prothrombotic versus antithrombotic substances) leading towards an excess of vasoconstriction, smooth muscle hyperplasia and pulmonary vascular remodelling [1][2][3]. In addition, disturbances of the normal balance between endothelial cell proliferation and endothelial cell apoptosis have been reported in idiopathic pulmonary arterial hypertension (PAH) [16,17].…”

“…The exact mechanisms of pulmonary arterial remodelling that lead to the onset and progression of PH are still largely unclear. However, many disease-predisposing factors and/or contributing factors have been identified, including inflammation, endothelial cell dysfunction, aberrant vascular wall cell proliferation and mutations in the bone morphogenetic protein-receptor type 2 (Bmpr2) gene [1][2][3].…”

Epigenetic regulation of pulmonary arterial hypertension

“…1 According to the 4th World Symposium on Pulmonary Hypertension in 2008, PAH includes idiopathic PAH, familial PAH and acquired PAH. 2 The latter arises in association with collagen vascular disease, portal hypertension, infection with the human immunodeficiency virus, drugs and toxins, and other conditions. This category can have significant venous or capillary involvement as a consequence of pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension of the newborn (PPHN).…”

“…This category can have significant venous or capillary involvement as a consequence of pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension of the newborn (PPHN). 2 The pulmonary circulation is a low-pressure, low-resistance and high-flow system that has a pivotal role in gas exchange and oxygen transport. The pulmonary arteries have thinner muscular media, and the tone of pulmonary vascular smooth muscle is lower than that of most systemic arteries.…”