Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Figure 1. Pulmonary artery remodeling, vascular resistance and pulmonary arterial hypertension (PAH) development. PAH results from a progressive increase in vascular resistance caused by pulmonary vascular remodeling. Molecular mechanisms behind the process of vascular remodeling are still not fully elucidated but endothelial cell (EC) injury is thought to be one of the early triggers. EC injury can be caused by shear stress, hypoxia and inflammation. Host factors such as genetic mutations and gender but also epigenetic factors and comorbidities are thought to play an important role in EC dysfunction. EC dysfunction leads to altered cell signaling that induces cellular processes such as EndoMT, apoptosis, and proliferation. In addition, changes are found in cell metabolism and in the secretion of vasoactive, coagulation and thrombotic factors. Additionally, vascular smooth muscle cells and fibroblasts are found to display a diseased cellular phenotype. EC dysfunction eventually promotes vasoconstriction, thrombus formation, neointima formation, muscularization, and the development of vascular lesions. As lumen size decreases, pulmonary vascular resistance increases and induces right…

Figure 2. Transforming growth factor-β (TGF-β) superfamily signaling in PAH. The bone morphogenetic protein (BMP)/TGF-β signaling pathway is an important factor in the existence of EC dysfunction in PAH. Decreased expression of BMPR2 but more importantly various mutations in the BMPR2/BMP-ligand axis are associated with specific changes in EC behavior such as increased proliferation and migration, but also structural changes that cause the loss of the protective EC barrier. In addition, the TGF-β superfamily signaling also plays an important role the initiation of EndoMT by triggering the overexpression of genes, like TWIST1, αSMA, and phospho-vimentin. Receptor-regulated Smads (R-Smads); Common mediator Smad (Co-Smad); Inhibitory Smads (I-Smads).

Figure 3. Endothelial dysfunction in PAH. PAH is characterized by endothelial dysfunction that causes an imbalance in the production of several endothelial-specific factors. The endothelium presents a pro-inflammatory phenotype with an increased expression of cytokines, a pro-thrombotic surface due to changes in the expression of clotting factors (e.g., TF) and increased expression of pro-thrombotic factors, and an imbalanced production of vasoactive factors that promote vasoconstriction. Upon endothelial cell injury, pulmonary artery- endothelial cells (PAECs) become dysfunctional and alter their secretion of cytokines and other factors that regulate coagulation, thrombosis, and vascular tone. A failure of PAECs in maintaining vessel homeostasis promotes vasoconstriction, thrombosis and inflammation that initiate PAH disease progression.

Figure 4. Endothelial to mesenchymal transition (EndoMT) in PAH. EndoMT in PAH is thought to be an important process contributing to vascular remodeling. Activation by transcriptional factors, hypoxia, haemodynamic forces, inflammation, and TGF-β/BMP pathway signaling pulmonary endothelial cells (PAECs) undergo cellular transition to a mesenchymal phenotype, in which PAECs lose endothelial markers and gain mesenchymal markers, such as αSMA and TWIST. These mesenchymal-like cells present an invasive character and hence contribute to vascular remodeling in PAH.

Figure 5. Epigenetics in PAH. In addition to genetic variations and other risk factors, such as gender, comorbidities, and environmental factors, epigenetic variations in PAH gain interest. Differences in DNA methylation profiles, increased histone acetylation and dysregulated miRNA expression in PAH patients point out a growing field in PAH research that provides better understanding of disease pathology.