Abstract
Pulmonary hypertension (PH) is a rare disease with a high morbidity and mortality rate. A number of systemic diseases and genetic mutations are known to lead to PH. The main features of PH are altered vascular relaxation responses and the activation of proliferative and anti-apoptotic pathways, resulting in pulmonary vascular remodeling, elevated pulmonary artery pressure, and right ventricular hypertrophy, ultimately leading to right heart failure and premature death. Important advances have been made in the field of pulmonary pathobiology, and several deregulated signaling pathways have been shown to be associated with PH. Clinical and experimental studies suggest that, irrespective of the underlying disease, endothelial cell disruption and/or dysfunction play a key role in the pathogenesis of PH. Endothelial caveolin-1, a cell membrane protein, interacts with and regulates several transcription factors and maintains homeostasis. Disruption of endothelial cells leads to the loss or dysfunction of endothelial caveolin-1, resulting in reciprocal activation of proliferative and inflammatory pathways, leading to cell proliferation, medial hypertrophy, and PH, which initiates PH and facilitates its progression. The disruption of endothelial cells, accompanied by the loss of endothelial caveolin-1, is accompanied by enhanced expression of caveolin-1 in smooth muscle cells (SMCs) that leads to pro-proliferative and pro-migratory responses, subsequently leading to neointima formation. The neointimal cells have low caveolin-1 and normal eNOS expression that may be responsible for promoting nitrosative and oxidative stress, furthering cell proliferation and metabolic alterations. These changes have been observed in human PH lungs and in experimental models of PH. In hypoxia-induced PH, there is no endothelial disruption, loss of endothelial caveolin-1, or enhanced expression of caveolin-1 in SMCs. Hypoxia induces alterations in membrane composition without caveolin-1 or any other membrane protein loss. However, caveolin-1 is dysfunctional, resulting in cell proliferation, medial hypertrophy, and PH. These alterations are reversible upon removal of hypoxia, provided there is no associated EC disruption. This review examined the role of caveolin-1 disruption and dysfunction in PH.
Highlights
Pulmonary hypertension (PH) is a serious disease with a high morbidity and mortality rate
This is not surprising, because in animal experimental studies, the pulmonary arterial endothelial damage including the loss of membrane proteins and the activation of proliferative pathways has been shown to occur before the onset of PH [4]
pulmonary arterial hypertension (PAH) patients with CAV1 mutations exhibit elevated serum CXCL10 levels [64]. These results indicate that inflammation plays a significant role in PH, and, importantly, caveolin-1 plays a critical role in modulating inflammatory responses
Summary
Pulmonary hypertension (PH) is a serious disease with a high morbidity and mortality rate. Part of the problem is that the patients are diagnosed relatively late, after they have already developed significant histopathological changes in the pulmonary vasculature [3] This is not surprising, because in animal experimental studies, the pulmonary arterial endothelial damage including the loss of membrane proteins and the activation of proliferative pathways has been shown to occur before the onset of PH [4]. The luminal surface of ECs is coated with glycocalyx that forms an important barrier; it prevents platelet and leukocyte cells’ adhesion and modulates permeability It mediates the shear-induced release of nitric oxide (NO) from ECs. In response to stress, endothelial glycocalyx is shed [11]. Recent studies have shown that the loss or dysfunction of caveolin-1 plays a significant role in the initiation and the progression of the pathogenesis of PH
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