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

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Abstract
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 (EM) 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 aEMof 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 (Kv), inward rectifier (Kir), calcium‐sensitive (KCa), and two‐pore (K2P) 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 Kv1.5, which depolarizesEM, 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. Kvexpression is also transcriptionally regulated by HIF‐1α and NFAT. Loss of PASMC Kv1.5 and Kv2.1 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 Kvexpression (via Kv1.5 gene therapy, dichloroacetate, or anti‐survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kvcurrent (including an oxygen‐sensitive component), whereas conduit PASMC current is a Kv/KCamosaic. 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.