Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling

Abstract

Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington's epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington's theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality.

Keywords: Endothelial to mesenchymal transition; cellular reprogramming; endothelial cells; pulmonary hypertension; remodelling.

Figure 1

The origin of the SM-like cells in pulmonary arterial remodelling. Resident vascular smooth muscle cells (SMCs) from the medial layer retain high cell plasticity and, under specific circumstances, undergo phenotypic switch towards a synthetic or “de-differentiated” state (A). Differentiated SMCs become highly proliferative and migratory. Circulating progenitor cells could be recruited to sites of vascular injury and assume a SM-like phenotype (B). Resident progenitor cells in the adventitia may also serve as a source of SM-like cells and contribute to the pathophysiological changes in vascular structure (C). Additionally, Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT) (D).

Figure 2

Cellular differentiation and reprogramming patterns. Waddington’s epigenetic landscape. Somatic cells take on a specific fate by compulsorily progressing from the pluripotent state to a terminal differentiated state (A). Transdifferentiation. A mature cell switches its phenotype and function to that of another mature differentiated cell type without undergoing an intermediate pluripotent state or becoming a progenitor cell (B). Dedifferentiation of reprogramming to pluripotency. Differentiated cells return to an immature state and regain pluripotency (C). EMT/EnMT; partial dedifferentiation. Cells change their specific fate, dedifferentiate and acquire a more immature, proliferative phenotype from another somatic lineage without converting to a pluripotent cell (D).