Abstract
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.
Highlights
The failure in the fetal-to-neonatal transition ensuing in a functional pulmonary circulation after birth results in pulmonary hypertension of the newborn, a syndrome that affects up to 6.8 per 1,000 of the births in lowlands (Walsh-Sukys et al, 2000), but whose prevalence could reach ∼10% of neonates under hypobaric hypoxia of the Andean Altiplano (Keyes et al, 2003; Peñaloza and Arias-Stella, 2007; Herrera et al, 2015)
The weight of the lambs used in the study was 4.90 ± 0.54– 5.82 ± 0.67 kg for animals assigned to the vehicle-treated group and 4.85 ± 0.14–6.73 ± 0.29 kg for those assigned to the 2-APB-treated group at the beginning and the end of the study, respectively
The mean SAP (mSAP), heart rate (HR), Cardiac output (CO), and systemic vascular resistance (SVR) were similar in control lambs and 2-APB-treated lambs along with the treatment (Figure 1)
Summary
The failure in the fetal-to-neonatal transition ensuing in a functional pulmonary circulation after birth results in pulmonary hypertension of the newborn, a syndrome that affects up to 6.8 per 1,000 of the births in lowlands (Walsh-Sukys et al, 2000), but whose prevalence could reach ∼10% of neonates under hypobaric hypoxia of the Andean Altiplano (Keyes et al, 2003; Peñaloza and Arias-Stella, 2007; Herrera et al, 2015). Survivors may have impaired neurological development and recurrent pulmonary hypertension later in life (Nair and Lakshminrusimha, 2014) Both fetal and postnatal pulmonary arteries quickly contract and develop a pathological remodeling in response to hypoxia (Gao and Raj, 2011; Dunham-Snary et al, 2017; Hussain et al, 2017). Conception and first 30% of gestation occurred at lowland; the last 70% of gestation and birth at 3,600 m.a.s.l. to return to the lowland at 2 days of postnatal age for the study (Herrera et al, 2010) Both models of perinatal hypoxia exposure showed increased mPAP, PVR, and hypoxic pulmonary vasoconstriction, right ventricular hypertrophy, and thickened pulmonary arterial walls compared with lowland healthy controls. SOCE allows replenishment of Ca2+ stores, but it can itself generate long-term Ca2+ signals
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