Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype.

Keywords: DNA damage; endothelial-to-mesenchymal transition; metabolism; microRNA; mitochondria; pulmonary arterial hypertension.

Figure 1

Metabolism in PAH. Metabolism in PAH is perturbed akin to what is observed in cancer. Glycolysis occurs when glucose is taken up by the glucose transporters-1 (GLUT-1) and -4 (GLUT-4), gets phosphorylated by hexokinase (HK), and goes through a series of reactions to produce pyruvate. Pyruvate is the substrate for pyruvate dehydrogenase (PDH) in the mitochondria to support glucose oxidation. Free fatty acids (FFA) are taken up by fatty acid transport protein-1 (FATP-1) and -6 (FATP-6) and transformed to acyl carnitines that are shuttled across the mitochondrial membrane by carnitine palmitoyltransferase-1 (CPT1) and transformed to acyl CoA by carnitine palmitoyltransferase-2 (CPT2). Acyl CoA is converted to acetyl CoA during β-oxidation. In PAH, there is increased aerobic glycolysis due to normoxic upregulation of HIF-1α, which upregulates pyruvate dehydrogenase kinase (PDK) to inhibit pyruvate dehydrogenase, and epigenetic regulation of the superoxide dismutase 2 (SOD2) gene. PFK, phosphofructokinase; PK, pyruvate kinase; LDH, lactate dehydrogenase; ROS, reactive oxygen species; ETC, electron transport chain.

Figure 2

Endothelial-to-mesenchymal transition. Endothelial-to-mesenchymal transition (EndoMT) occurs when the endothelium is exposed to environmental stressors that increase levels of transforming growth factor-β (TGFβ), tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). These factors activate a select population of endothelial cells, which lose their endothelial markers (i.e., CD31, vascular endothelial cadherin (VE-cadherin), and von Willibrand factor (vWF)) and lose tight gap junctions between cells (double lines). These endothelial cells then express α-smooth muscle actin (α-SMA) and vimentin. Cells may also acquire a mesenchymal phenotype and express fibronectin, N-cadherin, and the EndoMT-related transcription factor Twist.