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

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.

Antenatal Dexamethasone Exposure Impairs Vascular Contractile Functions via Upregulating IP3 Receptor 1 and Cav1.2 in Adult Male Offspring

“…[8][9][10][11] Animal models have shown that antenatal glucocorticoids exposure can lead to hypertension and arterial stiffness in later life periods beyond childhood. [8][9][10][11] As a surrogate end point for vascular risk, vascular contractility is closely related to occurrence and progress of many vascular diseases, particularly hypertension. Of critical importance, a number of studies in laboratory animals indicated antenatal dexamethasone treatment impairs vascular contractility in adult offspring 10,11 ; however, limited information is currently available regarding the underlying mechanisms.…”

“…[8][9][10][11] As a surrogate end point for vascular risk, vascular contractility is closely related to occurrence and progress of many vascular diseases, particularly hypertension. Of critical importance, a number of studies in laboratory animals indicated antenatal dexamethasone treatment impairs vascular contractility in adult offspring 10,11 ; however, limited information is currently available regarding the underlying mechanisms. As a dominant cell type that constitutes the vascular wall, vascular smooth muscle cells (SMCs) are key initiators of vascular contractility.…”

Recent Advances in Studies on the Role of Neuroendocrine Disorders in Obstructive Sleep Apnea–Hypopnea Syndrome-Related Atherosclerosis

“… 113 Glucocorticoids increase the sensitivity of blood vessels to endothelium-derived vasoconstrictors, such as catecholamines and endothelin-1. 114 Moreover, glucocorticoids can promote AS development by promoting insulin resistance, dyslipidemia, and hypertension. Glucocorticoids increase the levels of procoagulant factors, mainly including factors VIII, IX, and von Willebrand factor, and impaired fibrinolysis, mainly including plasminogen activator inhibitor-1.…”

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

“…The role of retinoic acid in modulating CD38 expression and cADPR levels in many cell types has been investigated extensively [ 32 , 83 ]. Betamethasone, another hormone, administered antenatally in sheep model leads to increased CD38 expression and contributes to postnatal hypertension suggesting a potential augmenting effect of CD38 in peripheral vascular resistance [ 84 ].…”