Endothelial-to-Mesenchymal Transition: An Evolving Paradigm and a Promising Therapeutic Target in PAH
Pulmonary arterial hypertension (PAH) is a complex and progressive disorder, which almost always leads to right heart failure and death1. PAH is invariably associated with a spectrum of structural changes in the pulmonary arteries: increased adventitial and medial thickness, eccentric and concentric intimal thickening, the obliteration and recanalization of arteries and the appearance of dilation lesions. Virtually all of these changes are characterized, to a greater or lesser degree, by increased numbers of cells expressing α-smooth muscle (SM)-actin. However, neither the origins of these cells nor the molecular mechanisms operating to cause their accumulation have been fully elucidated. Traditionally it has been thought that the α-SM-actin expressing (SM)-like cells that accumulate in the above-mentioned vascular lesions were derived from proliferative expansion of resident vascular media SM cells (SMCs) or adventitial fibroblasts through the processes of de-differentiation of the former or differentiation of the latter. Through the years, however, this concept has been challenged by experimental data in not only the lung but also in the heart, kidney, and liver, demonstrating many possible sources of α-SM-actin expressing cells, including differentiation of resident vascular progenitor cells, recruitment of circulating progenitors or multi-functional inflammatory cells (fibrocytes), and finally the possibility that endothelial cells can transition into mesenchymal SM-like phenotype in a process recapitulating their developmental capabilities2, 3. Studies by Ranchoux et al.4, and now by Hopper et al. in this issue of Circulation5, provide convincing experimental evidence that endothelial-to-mesenchymal transition (EndMT) occurs in the setting of PAH/PH in both humans and animal models and potentially constitutes a target against which specific therapeutic agents could be utilized to abrogate the process and improve the status of the patient with PAH.
- endothelial cell
- endothelial cell differentiation
- endothelial dysfunction
- pulmonary hypertension
- Received March 31, 2016.
- Accepted April 1, 2016.