Pulmonary Vascular Signaling in Pulmonary Hypertension: Potential Role of Endothelial Ca 2+ Signaling in Cellular Senescence and Inflammasome Activation

This review focuses on describing the potential pathogenic roles of endothelial Ca2+ and K+ signaling in the development and progression of pulmonary hypertension through its putative regulation of cellular senescence and inflammasome activation. Ca2+ influx through mechanosensitive and receptor-operated cation channels and Ca2+ release from the endoplasmic reticulum are involved in upregulating the cell cycle inhibitors p53, p21, and p16 (which result in cellular senescence) by activating the AKT/mTORC1 pathway in lung vascular endothelial cells. A rise in cytosolic Ca2+ concentration, resulting from Ca2+ influx and release in lung vascular endothelial cells, is also necessary to activate both canonical (NLRP3 NOD-like receptor family pyrin domain-containing 3) and noncanonical inflammasomes, thereby promoting vascular and perivascular inflammation. Furthermore, K+ efflux through multiple types of K+-permeable channels and pores (eg, K+ ionophores, toxin-formed pores/channels, nonselective cation channels, and Ca2+-activated K+ channels) is sufficient for canonical (NLRP3) inflammasome activation. The senescent endothelial cells release senescence-associated secretory phenotype factors that subsequently cause endothelial-to-mesenchymal transition in adjacent endothelial cells and promote cell proliferation/migration in adjacent smooth muscle cells and (myo)fibroblasts, leading to vascular remodeling and occlusive intimal lesions, and pulmonary hypertension.