Potassium channel diversity in the pulmonary arteries and pulmonary veins: Implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension

This review describes the ionic heterogeneity manifest in the pulmonary circulation, particularly as it pertains to hypoxic pulmonary vasoconstriction (HPV) and pulmonary arterial hypertension (PAH). Heterogeneity in potassium (K+) channels, key regulators of vascular tone, cell proliferation, and apoptosis rates, contribute to the diverse response of vascular segments to hypoxia and to the localization of pathological changes in PAH. Pulmonary artery (PA) and pulmonary vein (PV) smooth muscle cells (SMC) express several K+ channel families, including calcium-sensitive (KCa), voltage-gated (Kv), inward rectifier (Kir), and 2-pore channels. Diversity is created by heterogeneous occurrence of alternatively spliced, mRNA species, assembly of heterotetrameric channels from diverse α-subunits, and association of channels with regulatory β-subunits. Local heterogeneity in transcription factor activity may underlie differences in channel expression. Enrichment of resistance PASMCs with O2-sensitive K+ channels, such as Kv1.5, partially explains the greater HPV in resistance versus conduit PAs. In addition, resistance PAs are unique in having mitochondria which dynamically alter production of reactive O2 species (ROS) in proportion to PO2, thereby regulating K+ channel activity and controlling expression through transcription factors, such as HIF-1α. In intraparenchymal PVs, a coaxial layer of cardiomyocytes encompasses a media of typical vascular SMCs. PV cardiomyocytes have rhythmic contraction and their Kir-enriched channels may be relevant to genesis of atrial arrhythmias and pulmonary edema. Kv channel expression is decreased in PAH, leading to elevations of cytosolic  K+ and Ca2+ that impair apoptosis and increase proliferation. Understanding ionic diversity may allow development of therapies that locally increase K+ channel current and expression to treat PHT.