Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity

Abstract

.-Excessive exposure of the fetus to maternally derived corticosteroids has been linked to the development of adult-onset diseases. To determine if early gestation corticosteroid exposure alters subsequent coronary artery reactivity, we administered dexamethasone (0.28 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) to pregnant ewes at 27-28 days gestation (term being 145 days). Vascular responsiveness was assessed in endothelium-intact coronary and mesenteric arteries isolated from steroid-exposed and age-matched control fetal sheep at 123-126 days gestation and lambs at 4 mo of age. Lambs exposed to maternal dexamethasone had higher mean arterial blood pressures than the age-matched controls (93 Ϯ 3 vs. 83 Ϯ 5 mmHg, P Ͻ 0.05). Mesenteric arteries from the steroid-exposed fetuses displayed diminished responses to ANG II, relative to controls. In 4-mo-old lambs, prenatal dexamethasone exposure significantly increased coronary artery vasoconstriction to ANG II, ACh, and U-46619, but not KCl. In contrast, postnatal mesenteric artery reactivity was unaltered by steroid exposure. Compared with fetal mesenteric reactivity, postnatal mesenteric reactivity to ANG II, phenylephrine, and U-46619 was diminished, whereas the response to 120 mmol/l KCl was heightened. Coronary artery ANG II receptor protein expression was not significantly altered by steroid exposure in either age group. These findings demonstrate that early-gestation glucocorticoid exposure programs postnatal elevations in blood pressure and selectively enhances coronary artery responsiveness to second messenger-dependent vasoconstrictors. Glucocorticoid-induced alterations in coronary vascular smooth muscle structure or function may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease.angiotensin II; coronary arteries; fetal programming; vascular smooth muscle THERE ARE EPIDEMIOLOGICAL links between poor fetal growth and the subsequent development of atherosclerosis. The concept of the fetal programming of adult disease found its inception through the work of Barker and colleagues (2). Their initial epidemiological data are supported by a number of international studies suggesting that lower birth weight, a potential marker for an adverse intrauterine environment, is an independent risk factor for the development of both hypertension and coronary artery disease (5,15,23).A number of animal models have been developed to ascertain the intrauterine factors that presage the development of cardiovascular disease and investigate the mechanisms involved. Protein restriction models in pregnant rats demonstrated that maternal undernutrition is associated with the development of hypertension in the offspring. Excessive fetal exposure to glucocorticoids, related to inhibition of the placental enzyme responsible for inactivation of maternal corticosteroids, 11␤-hydroxysteroid dehydrogenase, may play a role in this response (13,16). Consistent with this hypothesis, inhibition of maternal corticosteroid synthesis, produced by administration of ...

Coronary Constriction to Angiotensin II Is Enhanced by Endothelial Superoxide Production in Sheep Programmed by Dexamethasone

“…Using this dex-exposure model, we have demonstrated that programmed sheep have coronary artery-specific increases in both superoxide production and angiotensin II (Ang II) responsiveness without alteration in Ang II receptor expression (6,7). Supporting the relevance of these findings, a role for renin-angiotensin system activation in programmed cardiovascular disease has now been demonstrated in studies that bridge animal models and experimental interventions (5,(7)(8)(9)(10)(11).…”

“…Supporting the relevance of these findings, a role for renin-angiotensin system activation in programmed cardiovascular disease has now been demonstrated in studies that bridge animal models and experimental interventions (5,(7)(8)(9)(10)(11). Among its cardiovascular effects, Ang II is a prototypical agonist for vascular NADPH oxidase, an enzyme linked to progression of atherosclerotic plaques through increased endothelial superoxide production (12,13).…”

“…Endothelium was removed from one arterial segment by rubbing. Rings were then mounted in wire myographs and equilibrated for 1 h, as previously described (7). After equilibration, arteries were constricted with KCl (120 mM) to normalize subsequent reactivity data.…”

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

“…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).…”