Mechanisms Of Vascular Dysfunction In Male Offspring Following Antenatal Exposure To Dexamethasone

Objectives:This study aimed to examine the effects and reveal its mechanism of antenatal exposure to clinically relevant doses of dexamethasone(DEX,synthetic glucocorticoids)on vascular function in adult male offspring.Methods:Pregnant SD rats were randomly separated into vehicle normal saline group(VEH)and dexamethasone exposed group(DEX),13 rats in each group.Five pregnant rats were taken from each group and mesenteric tissues of fetuses were collected by cesarean section on gestational day 21.In each group,8 pregnant rats would been given the natural delivery and healthy offspring of adult male rats who develop normally at 20 weeks of age were used for experiments.RT-PCR and Western-blot were used to study the molecular biology of fetal rats tissues.In the two groups,vascular tension detection system was used to test the vasoconstriction response of mesenteric artery to phenylephrine in the progeny.Smooth muscle cells were isolated for electrophysiological experiments,by using the PKC pathway inhibitor(GF,GF109203X),endoplasmic reticulum calcium atpase inhibitor(TG,Thapsigargin),endoplasmic reticulum ryanodine receptors inhibitor(RYR,Ryanodine),endoplasmic reticulum IP3 receptors inhibitor(2-APB,2-aminoethyl diphenylborinate),L-type calcium channel inhibitors(Nifedipine),L-type calcium channel agonist(Bayk8644)to explored the change of relevant pathways about dysfunction of vasoconstriction,and investigated the change of related molecular mechanism from the level of cellular electrophysiology.The expression levels of related genes and proteins in offspring mesenteric artery tissues were detected by the use of RT-PCR and Western-blot.Results:In the DEX group,the mesenteric artery of the progeny had a significantly stronger vasoconstriction response to phenylephrine(PE)than that of the VEH group.In both groups,GF,TG and RYR partially inhibited the vasoconstriction response induced by PE,but they did not eliminate the vasoconstriction difference which caused by PE.However,both 2-APB and Nifedipine obviously inhibited vasoconstriction response which mediated by PE and eliminated the difference in vasoconstriction response between the two groups.Compared with the VEH group,the vasoconstriction response of mesenteric artery to Bayk8644 was significantly enhanced in the DEX group.Compared with VEH group,the Cavl.2 channel current density of vascular smooth muscle cells in DEX offspring were significantly higher.Additionally,the increased Cav1.2 channel current density caused by PE in DEX group were enhanced more obviously.Compared with VEH group,mRNA and protein expression levels of IP3R1 and Cav1.2 were increased in fetal rats and adult mesenteric artery tissues in the DEX group.However there were no significant differences in mRNA and protein expression levels of IP3R2,IP3R3 and Cav3.2 between the two groups.Conclusions:Antenatal GCs exposure enhanced PE-mediated mesenteric artery vasoconstriction,which was related to IP3-Ca2+ pathway activated by the up-regulated expression of IP3R1 and Cav1.2.