Journal of Developmental Origins of Health and Disease

Original Article

Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling

J.-H. Leea1a2, J. Zhanga1, G. A. Massmanna1 and J. P. Figueroaa1 c1

a1 Department of Obstetrics and Gynecology, Center for Research in Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

a2 Department of Obstetrics and Gynecology, Chonbuk National University Medical School, Jeonju, South Korea

Abstract

Antenatal steroid administration is associated with hypertension in adult life; however, the mechanisms underlying this phenomenon are unclear. The aim of this study was to further characterize the effects of antenatal glucocorticoid exposure on the endothelin (ET-1) system, specifically to ascertain the role of the cyclic adenosine diphosphate ribose (cADPR)/ryanodine receptor pathway in the increased sensitivity to ET-1 observed in the offspring exposed to antenatal glucocorticoids. Pregnant sheep were randomly treated with betamethasone (Beta; 0.17 mg/kg) or vehicle at 80 and 81 days of gestation. In adults, we studied endothelium-denuded arterial segments of the brachial arteries. ET-1-induced vasoconstriction was significantly higher in the arteries from Beta sheep (F=3.5, P<0.05). Inhibition of ADP-ribosyl cyclase with 2-2'-dihydroxy-azobenzene significantly decreased the ET-1-induced contraction in Beta but not in vehicle-treated sheep. Nicotinamide attenuated ET-1 contraction in both, but it was significantly more pronounced in the Beta-treated sheep. No significant differences were observed following KCl-induced (6.25–75 mM) contraction. Nicotinamide (10 mM) significantly attenuated the KCl-induced vasoconstriction in both groups. In KCl (62.5 mM)-constricted arteries, the effect of nicotinamide (NIC) was significantly greater in the vehicle-treated sheep (50% relaxation v. 40% relaxation; t=2.2, P<0.05). In contrast, the sodium nitroprusside (SNP) relaxation was not statistically different. An additive effect was observed when NIC and SNP were used in combination and it was also more pronounced in vehicle-treated sheep. We conclude that the increased response to ET-1 is mediated by activation of the CD38/cADPR signaling pathway. Further studies are required to identify the effectors downstream from cADPR affected by exposure to antenatal steroids.

(Received August 15 2013)

(Revised October 08 2013)

(Accepted November 01 2013)

Key words

  • animal;
  • large animals;
  • molecular/cellular

Correspondence

c1 Address for correspondence: Jorge P. Figueroa, Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. (Email figueroa@wakehealth.edu)

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