Prenatal High-sucrose Diet Induced Mesenteric Vascular Dysfunction In Aged Male Offspring And Its Underlying Mechanisms

Background:There is an increase in the population of women with over-nutrition during pregnancy due to the improvement of economic level.Adverse intrauterine conditions could increase susceptibility of offspring to multiple chronic diseases,including diabetes,hypertension,and stroke.Previous work reported that prenatal high-sucrose(HS)diet could elevate blood glucose level and lead to vascular dysfunction in the adolescent male offspring rats,which was linked to the inhibited functions of large-conductance Ca2+-activated K+ channels(BK).Vascular aging is an important pathological basis for organs senescence during the aging process,and it has become the common pathogenesis of various chronic degenerative diseases.However,the underlying mechanism about whether and how prenatal HS diet affects vascular aging in the offspring is still unknown.This study aimed to evaluate the effect of maternal HS diet during pregnancy on the vascular function of mesenteric artery and the underlying mechanisms in the aged male offspring rats.The data gained will offer new information for early prevention of vascular disorder in offspring suffering from prenatal malnutrition and provide new clues on relevant targets for clinical translational medicine.Methods:One SPF female rat(4 months old)mated with two SPF male rats(4months old).The day vaginal plugs detected was regarded as the first day of gestation.Pregnant rats were randomly divided into control(CON:normal water and standard food,N=20)and high-sucrose group(HS:20%sucrose solution,N=20).Following natural delivery,male offspring rats were raised with normal water and standard food for 20 months.Femoral artery cannulation technique,microvascular function detection technique and vascular myogenic tension technique were used to evaluate the effect of high glucose diet during pregnancy on the structure and function of mesenteric artery in aged male offspring.Patch clamp technique and molecular biology technology were used to further investigate the underlying mechanisms about cellular phenotype alteration and dysfunction of ion channels in vascular smooth muscle cells(VSMCs)in mesenteric arteryResults:1)Compared with CON,aged male offspring from HS exhibited elevated body weight(P<0.05),fasting insulin level and insulin resistance index.Both diastolic pressure and mean arteric pressure were significantly increased,although systolic pressure showed no difference in offspring from HS group.2)Expression of matrix metalloproteinase 2 of mesenteric arteries was increased in HS group while expression of its tissue inhibitors of metalloproteinase(TIMP1)was reduced(P<0.05),indicating that extra cellular matrix(ECM)was remodeled.Both phenylephrine-stimulated vascular contractions and pressure-induced myogenic responses in mesenteric arteries were remarkably weakened,indicating vascular dysfunction may be related to the decreased function of L-type calcium channel in mesenteric artery.3)Expressions of contractile phenotype genes,such as ?-smooth muscle actin(?-SMA),were obviously decreased.What's more,insulin/insulin receptor/phosphoinositide 3-kinase(PI3K)signaling pathway(IR/IRS-1/PI3K)was downregulated.Tests of the primary smooth muscle cells from mesenteric artery demonstrated that both insulin signaling pathway and L-type calcium channel could regulate the cell phenotype of VSMCs.Conclusion:Prenatal HS diet induced vascular dysfunction and vascular stiffness of mesenteric arteries in aged male offspring by inhibiting Cav1.2 function and PI3K-associated contractile phenotype of VSMCs.