Proliferative Versus Degenerative Paradigms in Pulmonary Arterial Hypertension: Have We Put the Cart before the Horse?

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 "cancerlike" 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.