Heterogeneity of hypoxia‐induced decrease in I K(V) and increase [Ca 2+ ] cyt in pulmonary artery smooth muscle cells

Abstract

Acute hypoxia causes pulmonary vasoconstriction by increasing cytoplasmic free Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC). Multiple mechanisms are involved in the hypoxia-induced increase in [Ca2+]cyt in PASMC. Isolated human and rat PASMC display heterogeneous phenotypes in terms of contractility, gene expression, proliferation/apoptosis, and migration. Heterogeneity is believed to be due in part to differential expression and function of ion channels. We observed that acute hypoxia reduced voltage-gated K+ (Kv) currents (IK(V)) and increased [Ca2+]cyt in 53% of rat PASMC. The sensitivity of IK(V) to hypoxia correlated with the expression level of KCNA5, a Kv channel subunit that participates in forming oxygen-sensitive Kv channels. Using single cell RT-PCR and voltage clamp techniques, we show here that KCNA5 mRNA expression in hypoxia-sensitive PASMC (i.e., acute hypoxia reduces IK(V)) is much greater than in hypoxia-insensitive cells (i.e., negligible effect IK(V)). These results suggest that a) different PASMC express varying levels of Kv channels, and b) the sensitivity of a PASMC to hypoxia partially depends on the expression level of KCNA5. In addition, the acute hypoxia-mediated increase in [Ca2+]cyt varied among PASMC, but the sensitivity of this Ca2+ response was not related to the resting [Ca2+]cyt level. An intrinsic mechanism in individual PASMC may be involved in the heterogeneous effect of hypoxia on [Ca2+]cyt in PASMC. The observations from this study suggest that the response heterogeneity of PASMC to hypoxia may be related to different expression level and functional sensitivity of Kv channels to hypoxia, and to differences in intrinsic mechanisms involved in regulating [Ca2+]cyt. (Research supported by grants from the NIH/NHLBI)