AJ, Reyes RV. Store-operated channels in the pulmonary circulation of high-and low-altitude neonatal lambs. Am J Physiol Lung Cell Mol Physiol 304: L540 -L548, 2013. First published February 15, 2013 doi:10.1152/ajplung.00024.2012.-We determined whether store-operated channels (SOC) are involved in neonatal pulmonary artery function under conditions of acute and chronic hypoxia, using newborn sheep gestated and born either at high altitude (HA, 3,600 m) or low altitude (LA, 520 m). Cardiopulmonary variables were recorded in vivo, with and without SOC blockade by 2-aminoethyldiphenylborinate (2-APB), during basal or acute hypoxic conditions. 2-APB did not have effects on basal mean pulmonary arterial pressure (mPAP), cardiac output, systemic arterial blood pressure, or systemic vascular resistance in both groups of neonates. During acute hypoxia 2-APB reduced mPAP and pulmonary vascular resistance in LA and HA, but this reduction was greater in HA. In addition, isolated pulmonary arteries mounted in a wire myograph were assessed for vascular reactivity. HA arteries showed a greater relaxation and sensitivity to SOC blockers than LA arteries. The pulmonary expression of two SOC-forming subunits, TRPC4 and STIM1, was upregulated in HA. Taken together, our results show that SOC contribute to hypoxic pulmonary vasoconstriction in newborn sheep and that SOC are upregulated by chronic hypoxia. Therefore, SOC may contribute to the development of neonatal pulmonary hypertension. We propose SOC channels could be potential targets to treat neonatal pulmonary hypertension.hypoxia; pulmonary vasoconstriction; pulmonary hypertension; 2-aminoethydiphenylborinate; pulmonary vascular reactivity PULMONARY ARTERIES HAVE AN intrinsic vasoconstrictor response to low oxygen levels when exposed to acute hypoxia. This is a reversible, rapid and physiological response, known as hypoxic pulmonary vasoconstriction (HPV), that redirects blood flow from poorly oxygenated to better oxygenated alveoli. Thus, when total lung is exposed to hypoxia, HPV results in an increase in pulmonary artery pressure (PAP) that reverses when normoxia is reestablished (31). However, exposure to chronic hypoxia produces an imbalance between vasodilator and vasoconstrictor mechanisms, and there is pulmonary vascular remodeling that includes proliferation of pulmonary artery myocytes among other cellular processes (46). The result is a pathological and persistent increase in pulmonary artery contractile tone and pulmonary arterial hypertension, which in many cases leads to right ventricular hypertrophy, right heart failure, and eventually death (13).In pulmonary artery smooth muscle cells, an increase in intracellular calcium concentration ([Ca 2ϩ ] i ) is essential for HPV, proliferation, and remodeling (13,19,20,42). This increase in [Ca 2ϩ ] i greatly depends on an influx of extracellular calcium (13, 59), which may enter the smooth muscle cell through store-operated channels (SOC) among other pathways (5,8,22,40). These are channels physiologically ...

Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg–1] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.