Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in KCa2.3 and KCa3.1 Channels

Abstract

ObjectiveIn vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension.Approach and ResultMale wild type and KCa3.1−/−/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1−/−/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype.ConclusionDespite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.

Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarisation in pulmonary hypertension

“…BKCa channel expression and function has been shown to be elevated in chronic hypoxic mice and PASMCs [27, 28]. In concert with the pulmonary hypertension model, for the first time, we have shown that the BKCa channel and β-subunits are upregulated in remodelled pulmonary arteries obtained by laser-captured microdissection from IPAH patients.…”

Down-regulation of KCa2.3 channels causes erectile dysfunction in mice

“…In previous studies of K Ca 2.3 T/T mice with and without doxycycline-treatment, only few studies have compared the results with wild type mice 17, 18, 45 , and it can be discussed whether the wild type or the upregulated K Ca 2.3 T/T (−Dox) mice are the correct controls animals to compare the responses with in animals with downregulation of the K Ca 2.3 channels. The K Ca 2.3  T/T channel mice are born with an overexpression of the K Ca 2.3 channel and that affects probably also the vascular structure and heart during the growth of the animals 45 . At 16 Hz stimulation of the cavernous nerve, the erectile responses are less compared to the WT both in the K Ca 2.3 T/T (−Dox) mice and the K Ca 2.3 T/T (+Dox) mice.…”

Genetic deficit of KCa3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation

“…K Ca 3.1 −/− and wt mice were derived from our breeding colonies (Si et al ., ; Lambertsen et al ., ; Wandall‐Frostholm et al ., ). All animal protocols or in vitro studies were performed in agreement with the ARRIVE guidelines and approved by the Danish animal care committee (permission 2011/561–2011; Kilkenny et al ., ; McGrath et al ., ).…”