Long-Term Maternal Hypoxia

Abstract

Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca 2þ ) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, the mechanisms of antenatal maternal hypoxia-related PPHN are unresolved. Because both LTH and 5-HT are associated with PPHN, we tested the hypothesis that antenatal maternal LTH can increase 5-HT-mediated PA contraction and associated extracellular Ca 2þ influx through L-type Ca 2þ channels (Ca L ), nonselective cation channels (NSCCs), and reverse-mode sodium-calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca 2þ imaging approaches on fetal lamb PA (*140 days of gestation) from normoxic ewes or those acclimatized to high-altitude LTH (3801 m) for *110 days. Long-term hypoxia reduced the potency but not the efficacy of 5-HT-induced PA contraction. Ketanserin (100 nmol/L), a 5-HT 2A antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 mmol/L), a 5-HT 1B/D inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for Ca L , NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca 2þ regardless of maternal hypoxia, NSCC was more important to contraction than Ca L , and reverse-mode NCX had little or no role in contraction. Long-term hypoxia also attenuated the effects of 2-APB and flufenamic acid and reduced Ca 2þ responses observed by imaging studies. Overall, LTH reduced 5HT 1B/D function and increased NSCC-related Ca 2þ -dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn.

Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses

“…After the initial one hour recovery period fetal pCO 2 , Hgb, and pH were similar between the groups (Table 1) Previous induced hypoxic ovine fetus models have been described using hyperthermia, hypoxic chambers, high altitude, and uterine artery embolization. 9,10 In contrast, animals in this study were identified as NOR or spontaneously HYP during the postoperative recovery period, and were studied over a 2 day period. HYP fetuses were identified as those with an SaO2 of ≤55% and evidenced a basal PaO2 of 16.1 mmHg on the study day, consistent with criteria for hypoxia utilized in previous studies of spontaneously hypoxic ovine fetuses.…”

Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

“…Our understanding of Ca 2+ signaling in fetal pulmonary arterial myocytes is still limited, but studies performed on fetal sheep pulmonary vascular myocytes illustrate that platelet activating factor (PAF) causes InsP 3 generation and Ca 2+ responses [77, 78]. This is substantiated by our own studies showing that ATP, phenylephrine and serotonin all cause Ca 2+ responses in pulmonary arterial myocytes from fetal sheep [64, 79]. Even still, ET-1-dependent activation of G protein coupled receptors can also induce RyR-generated Ca 2+ sparks [80], illustrating the complexity of Ca 2+ signaling within pulmonary vascular myocytes.…”

“…Moreover the fetal circulation is also characterized by progressive changes in vasore-activity. For example, we find that ovine fetuses have reduced constriction to membrane depolarization with high potassium [63] or serotonin [64, 65] as compared to adults. Also in the ovine fetus, vasoreactivity increases in late gestation (136-146 days) compared to early gestation (94-101 days), with increased hyperoxia-induced vasodilation and pulmonary vascular blood flow [66].…”

“…These channels are activated by membrane depolarization due to GPCR stimulation or acute hypoxia. We find L-type Ca 2+ channels provide for roughly one-quarter of the contraction due to serotonin [64] and potassium-induced membrane depolarization in sheep fetal pulmonary arteries [63]. L-type Ca 2+ channel blockers in piglets also dramatically reduce pulmonary arterial pressures and increase flow in vivo [81].…”

“…L-type Ca 2+ channel blockers in piglets also dramatically reduce pulmonary arterial pressures and increase flow in vivo [81]. Although L-type Ca 2+ channel activity is central to pulmonary arterial contractility, data shows that non-selective cation channels are also important to fetal pulmonary arterial Ca 2+ signaling and arterial reactivity [64, 82]. In particular, we found that inhibition of non-selective cation channels with SKF96365 blocked about one-half of the serotonin-mediated contraction above the portion sensitive to the L-type Ca 2+ channel inhibitor nifedipine [64].…”