1. Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension
- Author
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Stenmark, Kurt R, Frid, Maria G, Graham, Brian B, and Tuder, Rubin M
- Subjects
Lung ,2.1 Biological and endogenous factors ,Aetiology ,Cardiovascular ,Animals ,Cell Differentiation ,Cell Plasticity ,Cell Proliferation ,Cellular Senescence ,Epithelial-Mesenchymal Transition ,Humans ,Hypertension ,Pulmonary ,Hypertrophy ,Inflammation Mediators ,Muscle ,Smooth ,Vascular ,Myocytes ,Smooth Muscle ,Phenotype ,Pulmonary Artery ,Signal Transduction ,Vascular Remodeling ,Progenitor cells ,Endothelial mesenchymal transition ,Inflammation ,Metabolism ,Senescence - Abstract
Pulmonary hypertension (PH) is the end result of interaction between pulmonary vascular tone and a complex series of cellular and molecular events termed 'vascular remodelling'. The remodelling process, which can involve the entirety of pulmonary arterial vasculature, almost universally involves medial thickening, driven by increased numbers and hypertrophy of its principal cellular constituent, smooth muscle cells (SMCs). It is noted, however that SMCs comprise heterogeneous populations of cells, which can exhibit markedly different proliferative, inflammatory, and extracellular matrix production changes during remodelling. We further consider that these functional changes in SMCs of different phenotype and their role in PH are dynamic and may undergo significant changes over time (which we will refer to as cellular plasticity); no single property can account for the complexity of the contribution of SMC to pulmonary vascular remodelling. Thus, the approaches used to pharmacologically manipulate PH by targeting the SMC phenotype(s) must take into account processes that underlie dominant phenotypes that drive the disease. We present evidence for time- and location-specific changes in SMC proliferation in various animal models of PH; we highlight the transient nature (rather than continuous) of SMC proliferation, emphasizing that the heterogenic SMC populations that reside in different locations along the pulmonary vascular tree exhibit distinct responses to the stresses associated with the development of PH. We also consider that cells that have often been termed 'SMCs' may arise from many origins, including endothelial cells, fibroblasts and resident or circulating progenitors, and thus may contribute via distinct signalling pathways to the remodelling process. Ultimately, PH is characterized by long-lived, apoptosis-resistant SMC. In line with this key pathogenic characteristic, we address the acquisition of a pro-inflammatory phenotype by SMC that is essential to the development of PH. We present evidence that metabolic alterations akin to those observed in cancer cells (cytoplasmic and mitochondrial) directly contribute to the phenotype of the SM and SM-like cells involved in PH. Finally, we raise the possibility that SMCs transition from a proliferative to a senescent, pro-inflammatory and metabolically active phenotype over time.
- Published
- 2018