Reversible or irreversible remodeling in pulmonary arterial hypertension

Abstract

Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of "reverse remodeling" (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling.

Figure 1.

Reversible or irreversible remodeling in pulmonary arterial hypertension (PAH): a hypothetical mechanism. This is a hypothetical figure of a cross-section of pulmonary arteries. Pulmonary vascular remodeling in PAH is characterized by the thickening of the media, a plexiform lesion, and muscularization. Such thickening is due to hyperplasia (proliferation) of phenotypically altered smooth muscle cells (SMC). A plexiform lesion is composed of apoptosis-resistant phenotypically altered endothelial cells (EC). Muscularization is the extension of new smooth muscle into the partially muscular and nonmuscular peripheral arteries. The SMC shift between a proliferative and nonproliferative phenotype may be attributed to cellular plasticity, rather than selective expansion of distinct cell subpopulations, suggesting that this form of vascular remodeling (i.e., likely medial thickening and muscularization) may be reversible. However, irreversible PAH in congenital heart disease is strongly associated with the impaired apoptotic regulation of EC and with endothelial damage, thus suggesting that vascular remodeling, which develops because of phenotypically altered EC (i.e., likely a plexiform lesion) may therefore be irreversible.