Proliferative Versus Degenerative Paradigms in Pulmonary Arterial Hypertension: Have We Put the Cart Before the Horse?
| Autor: | Duncan J. Stewart, Virgilio J. J. Cadete, Rafael Godoy, Ketul R Chaudhary, Mohamad Taha |
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| Rok vydání: | 2017 |
| Předmět: |
Pathology
medicine.medical_specialty Physiology Angiogenesis Hypertension Pulmonary 030204 cardiovascular system & hematology Biology Pulmonary Artery Vascular Remodeling Microcirculation 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Cell Proliferation Lung Cell growth medicine.disease Pulmonary hypertension Warburg effect Endothelial stem cell medicine.anatomical_structure 030228 respiratory system Microvascular Rarefaction Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation research. 120(8) |
| ISSN: | 1524-4571 |
| Popis: | Pulmonary arterial hypertension is believed to be a proliferative disease, triggered by endothelial cell injury and apoptosis and leading to the formation of occlusive vascular lesions caused by growth-dysregulated “cancer-like” cells. However, the current experimental and clinical evidence is not entirely consistent with this paradigm and suggests an alternate interpretation, specifically that microvascular rarefaction may be due to a degenerative process, driven by sustained endothelial cell apoptosis. The “degenerative” paradigm has important implications, not the least of which is that proliferative lesions may be a secondary manifestation of disease rather than the primary cause of microvascular rarefaction, and that regenerative strategies may be needed to restore the microcirculation in established disease . Although there remains much debate about the precise mechanisms of pulmonary arterial hypertension, it is generally accepted that there is functional microvascular rarefaction, resulting in a marked decrease in pulmonary vascular cross-sectional area. Two distinct, and seemingly mutually exclusive, mechanisms have been proposed for the loss of lung microvasculature. The first is a proliferative process that leads to arteriolar occlusion and obliteration, and the second is a degenerative process that leads to drop-out and loss of fragile lung vasculature. Let’s first consider the proliferative hypothesis. The so-called “cancer paradigm” of pulmonary arterial hypertension (PAH) is based on the idea that dysregulated endothelial cell (EC) growth can lead to disordered angiogenesis with the heaping up of intimal cells within the lumen causing arteriolar occlusion and obliteration. Indeed, dysregulated vascular cell growth is integrally linked to the development of plexiform lesions, which represent hallmark features of PAH. This is supported by evidence of changes in biochemical and molecular cellular activity in PAH, similar to those seen in cancer, including a shift in glucose metabolism from mitochondrial glucose oxidation to glycolysis (Warburg effect), activation of cell growth pathways, increased expression of … |
| Databáze: | OpenAIRE |
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