Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension

Abstract

. Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension. Am J Physiol Regul Integr Comp Physiol 289: R1169 -R1176, 2006. First published June 16, 2005 doi:10.1152/ajpregu.00369.2005.-Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces organ-specific alterations in postnatal cardiovascular physiology. To determine whether early gestation corticosteroid exposure alters coronary reactivity before the development of systemic hypertension, dexamethasone (0.28 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term, 145 days). Vascular responsiveness was assessed in endotheliumintact coronary arteries isolated from 1-wk-old steroid-exposed and age-matched control lambs (N ϭ 6). Calcium imaging was performed in fura 2-loaded primary cultures of vascular smooth muscle cells (VSMC) from the harvested coronary arteries. Early gestation steroid exposure did not significantly alter mean arterial blood pressure or coronary reactivity to KCl, thromboxane A 2 mimetic U-46619, or ANG II. Steroid exposure significantly increased coronary artery vasoconstriction to acetylcholine and endothelin-1. Vasodilatation to adenosine, but not nitroprusside or forskolin, was significantly attenuated following early gestation steroid exposure. Endothelin-1 or U-46619 stimulation resulted in a comparable increase in intracellular calcium concentration ([Ca 2ϩ ]i) in coronary VSMC isolated from either dexamethasone-treated or control animals. However, the ANG II-or KCl-mediated increase in [Ca 2ϩ ]i in control VSMC was significantly attenuated in VSMC harvested from dexamethasone-treated lambs. Coronary expression of muscle voltage-gated L-type calcium channel ␣-1 subunit protein was not significantly altered by steroid exposure, whereas endothelial nitric oxide synthase expression was attenuated. These findings demonstrate that early gestation glucocorticoid exposure elicits primary alterations in coronary responsiveness before the development of systemic hypertension. Glucocorticoidinduced alterations in coronary physiology may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease. calcium imaging; endothelium; endothelial nitric oxide synthase; fetal programming EXPOSURE OF THE EARLY GESTATION ovine fetus to exogenous glucocorticoids induces organ-specific changes in postnatal cardiovascular physiology. The hypertensive aspect of this model of fetal programming was first described by Dodic et al. in 1998 (3). In their studies, the offspring of ewes given dexamethasone for 48 h beginning at 27 days gestation (term, 145-150 days) were hypertensive at 4 mo of age and remained hypertensive at 10 and 18 mo of age, despite normal intrauterine and postnatal growth. Using an identical model, we recently reproduced the hypertensive phenotype and demonstrated unique alterations in coronary artery reactivity (17). More speci...

Early Dexamethasone Treatment Induces Placental Apoptosis in Sheep

“…[6][7][8][9][10] Human fetuses with CAH, who had received dexamethasone (DEX), had normal preand postnatal growth 11 but showed more shyness, greater emotionality, and less sociability than unexposed children. 12 Previous studies in sheep have shown that maternal intravenously DEX treatment between 26 and 28 days of gestation (dG) did not result in fetal organ weight changes at 130 dG 13 but were associated with enhanced coronary artery vascular reactivity with 4 months of age, 14 altered brain renin-angiotensin function 15 and hyperinsulinemia in response to glucose challenge at the age of 4 years. 16 Female offspring demonstrated hypertension, which was still evident at the age of 7 years.…”

Endothelial Superoxide Production Is Altered in Sheep Programmed by Early Gestation Dexamethasone Exposure

“…We hypothesized that early gestation dexamethasone (DEX) exposure, an ovine model of fetal programming with impaired coronary endothelial-mediated vasodilation [2,3] , is associated with increased coronary, mesenteric and carotid artery superoxide anion levels. We further evaluated the biologic significance of regional ROS production through evaluation of markers of oxidative injury within adjacent organs susceptible to programming insults, including the heart, liver and brain [8] .…”

Antenatal Betamethasone Administration Has a Dual Effect on Adult Sheep Vascular Reactivity

“…Sheep exposed to maternal betamethasone at 26 -28 d gestation have an elevation in blood pressure by 3 mo of age that amplifies later in adult life (2,9,26,27). In this model of fetal programming, coronary artery response to ET-1 was shown to be enhanced in 1-wk newborns and also at 5 mo of age (2,3). Repeated weekly exposure to low doses of maternally administered dexamethasone starting at 103 d of gestational age resulted in increased sensitivity to ET-1 in skeletal muscle arteries of 119 dGA fetuses, (28) with this alteration persisting postnatally up to 5 mo of age (4).…”

“…Evidence from animal models of fetal programming indicates that antenatal glucocorticoids have adverse cardiovascular effects in the adult offspring, with alterations in vascular reactivity being a common finding in animal models across several species. In sheep, antenatal exposure to dexamethasone at 27-28 dGA results in adult hypertension and alterations in mesenteric artery vascular reactivity in 123-126 dGA fetuses, and in coronary reactivity in 1-wk-old and 4-mo-old lambs (2,3). Repeated weekly exposure to low doses of dexamethasone starting at 103 dGA does not produce changes in blood pressure, but it does alter femoral artery sensitivity to ET-1 and to acetylcholine (ACh) in 5-mo-old lambs (4).…”

“…Several contributing factors for the development of hypertension have been proposed, i.e. increases in cardiac output (9), in sodium retention (10,11), in sympathetic outflow (12), and altered vascular reactivity (2,3). ET-1 is the main endothelin generated in the endothelium and induces vasoconstriction, cell proliferation, and hypertrophy through the stimulation of smooth muscle ET A receptors and vasorelaxation through stimulation of endothelial ET B receptors (13).…”