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 Ca 2+ and K + signaling in the development and progression of pulmonary hypertension through its putative regulation of cellular senescence and inflammasome activation. Ca 2+ influx through mechanosensitive and receptor-operated cation channels and Ca 2+ 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 (Ak strain transforming/mammalian target of rapamycin) pathway in lung vascular endothelial cells. A rise in cytosolic Ca 2+ concentration, resulting from Ca 2+ influx and release in lung vascular endothelial cells, is also necessary to activate both canonical (NLRP3 [nucleotide-binding oligomerization domain-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 Ca 2+ -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.