The role of K⁺ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: Implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension

Potassium channels are tetrameric, membrane-spanning proteins that selectively conduct K⁺ at near diffusion-limited rates. Their remarkable ionic selectivity results from a highly-conserved K⁺ recognition sequence in the pore. The classical function of K⁺ channels is regulation of membrane potential (E_M) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K⁺ egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a E_M of about -60 mV. It has been recently discovered that K⁺ channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage-gated (K_v), inward rectifier (K_ir), calcium-sensitive (K_Ca), and two-pore (K_2P) channels. Certain K⁺ channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen-sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits K_v 1.5, which depolarizes E_M opens voltage-sensitive, L-type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia-inhibited K⁺ currents are not seen in systemic arterial SMCs. K^v expression is also transcriptionally regulated by HIF-1α and NFAT. Loss of PASMC K_v 1.5 and K_v 2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K⁺, thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring K_v expression (via K_v 1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous K_v current (including an oxygen-sensitive component), whereas conduit PASMC current is a K_v/K_Ca mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K⁺ channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH.