Abstract
Background: Fetal programming of adult diseases, including coronary artery disease, may be a consequence of fetal exposure to increased levels of maternally derived glucocorticoids. In an established ovine model, early gestation glucocorticoid exposure alters postnatal coronary artery vascular reactivity. This programming effect may be related to modifications in intracellular calcium regulatory responses.
Hypothesis: To determine if early gestational glucocorticoid exposure alters agonist-induced cytosolic calcium concentrations in coronary artery vascular smooth muscle (VSM).
Methods: Dexamethasone (dex, 0.28 mg/kg/d IV for 48 h) was administered to pregnant ewes at 27–28 days gestation (term 145 d). Ewes were allowed to deliver and the offspring and control lambs studied at a postnatal age of 12 ± 3 d (n=3 for each group). Intracellular calcium responses of primary cultured coronary and carotid VSM cells to a variety of agonists were determined in Fura-2 (a fluorescent Ca2+ indicator) loaded cells using a calcium imaging system (n = 8–40 cells for each condition).
Results: Baseline [Ca2+]i was similar in control and dex-exposed coronary VSM. Dex-exposed coronary VSM displayed decreased peak calcium responses to angiotensin II (1uM) and bradykinin (1 uM) compared to controls; peak responses to endothelin-1 (1 uM) and the thromboxane agonist U46619 (10 UM) were similar in both groups. KCl (90mM) caused an increase in [Ca2+]i (322 ± 35 nM) in control VSM but had no effect on dex VSM. The [Ca2+]i response to U46619 in control but not dex VSM was attenuated by the calcium channel blocker nifedipine (10 uM). Conversely, KCl increased [Ca2+]i in dex-exposed carotid VSM, and nifedipine decreased the calcium response to U46619. Dex also enhanced changes in [Ca2+]i in response to angiotensin II and U46619 in carotid VSM.
Conclusion: Early gestation glucocorticoids program altered regulation of VSM [Ca2+]i in a vessel-specific manner. In particular, dex diminished apparent function of voltage-gated calcium channels in coronary but not carotid VSM. These observations suggest a mechanism whereby an altered in-utero environment may predispose to coronary artery dysfunction later in life.
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Segar, E., Roghair, R., Lamb, F. et al. Early Gestation Dexamethasone Exposure Alters Calcium Transients in Coronary Vascular Smooth Muscle Cells in Newborn Lambs.. Pediatr Res 56, 669 (2004). https://doi.org/10.1203/00006450-200410000-00037
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DOI: https://doi.org/10.1203/00006450-200410000-00037