Alteration Of Vasoreactivity Of Mesenteric Arterioles In Offspring Of Gestational Diabetes

Metabolic reprogramming and epidemiological studies have found that the incidence of metabolic syndromes such as obesity,glucose and lipid metabolism disorders,and hypertension in the offspring of diabetes increases significantly in adulthood.The occurrence and development of hypertension is related to the abnormal function of resistance blood vessels,including increased vascular tone and vasodilation dysfunction.The vasodilation function includes endothelium-dependent relaxation and endothelium-independent relaxation.The former is respectively mediated by nitric oxide(NO),prostacyclin(PG)and endothelium-derived hyperpolarizing factor(EDHF),and the latter is related to the expansion of smooth muscles.The effect of the active substance is related.At present,studies on vascular endothelial damage from NO and PG sources in the offspring of diabetes are relatively extensive,while the number of studies on abnormal endothelial dysfunction derived from EDHF is limited.Previous studies have shown that C-type natriuretic peptide(CNP)mediates EDHF-derived endothelial relaxation function,and its effect increases with the decrease of blood vessel diameter.Our previous studies on the epigenetic changes of the pancreas in the offspring of gestational diabetes suggest that the Npr2 gene has hypermethylation changes,which encodes the type B CNP receptor(NPR-B)on smooth muscle cells,so the offspring of diabetes is vascular reactivity.In addition to the impaired endothelial diastolic function,whether the abnormality involves the abnormal expression or activity of the receptors of CNP and other vasoactive substances on smooth muscle remains to be further studied.This study aims to establish a diabetic pregnant mouse model by intraperitoneal injection of streptozotocin(STZ)on day 0 of pregnancy,and then compare the offspring of Gestational Diabetes(DMO)with normal blood glucose pregnant mice.Offspring of Control Mothers(CMO)received long-term high-fat diet intervention(16 weeks)to accelerate the progression of endothelial injury and observe whether DMO is more prone to abnormal glucose tolerance,arterial blood pressure and microvascular function than CMO.Through blood pressure and glucose tolerance tests,compare the changes in blood pressure regulation and glucose metabolism Phennotypes induced by high-fat diet in CMO and DMO in adulthood;compare the third-level branches of CMO and DMO mesenteric arteries by in vitro microvascular ring tension detection technology.Reactivity of arterioles to Phennylephrine(Phen),acetylcholine(ACh),sodium nitroprusside(SNP)and exogenous CNP.This topic aims to determine whether high-fat diet aggravates vascular endothelial function damage and CNP-mediated smooth muscle diastolic dysfunction of EDHF-derived diabetic offspring through the study of microvascular reactivity,thereby exposing epigenetic factors and secondary adverse factors in adulthood Provide experimental basis for the offspring’s vascular injury,and provide theoretical support for advocating healthy diet to maintain the offspring’s vascular function.Objective: To investigate the changes in vasoconstriction and diastolic function induced by DMO and CMO high-fat diet,which are the epigenetic changes induced by intrauterine hyperglycemia exposure to damage the offspring’s vascular function,especially the abnormal diastolic function and exogenous sources of EDHFThe experimental support provided by sexual CNP-mediated changes in smooth muscle diastolic function provides a theoretical basis for the study of generational transmission of diabetic cardiovascular disease.Methods:(1)Male DMO and CMO were randomly grouped and induced by highfat diet.They were: DMO offspring fed high-fat diet(DMO+HFD),CMO offspring fed high-fat diet(CMO+HFD);(2)Through the tail artery blood pressure monitoring,the aortic intubation blood pressure test,and the intraperitoneal glucose tolerance test(Intraperitoneal Glucose Tolerance Test,IPGTT),the differences in blood pressure and glucose tolerance between DMO and CMO were compared;(3)The microvascular tension detection technology was compared.The Phen-mediated contractile function of the mesenteric arterioles of the two groups of offspring rats;(4)The endothelial intact mesenteric arterioles with or without inhibitor NG-nitro-L-arginine Methyl Ester,LNAME)and Indomethacin(Indomethacin,Indo)pretreatment with ACh-mediated endothelium-dependent relaxation;(5)Endothelialized mesenteric arterioles SNP and CNP-mediated smooth muscle-dependent vasodilation.Results: Compared with the CMO+HFD group,the DMO+HFD group:(1)Relatively increased blood pressure;(2)Glucose tolerance was significantly weakened;(3)Phen-induced different mesenteric arteriole contractions had no significant difference;(4)Endothelial origin vasodilation effect:(1)Without pretreatment with inhibitors(L-NAME+Indomethacin),the vasodilation function induced by ACh of the mesenteric arterioles is weakened,and there is no significant difference in the maximum relaxation effect.(2)After pretreatment with inhibitor(L-NAME+Indomethacin),the endothelial relaxation effect of EDHF source is weakened,and the maximum effect is significantly reduced;(5)Smooth muscle-dependent vasodilation effect:(1)SNPmediated diastolic function of endothelial mesenteric arterioles is not obvious difference;(2)Exogenous CNP-mediated diastolic function of the deendothelized mesenteric arterioles was significantly weakened.Conclusion: Compared with CMO male offspring,DMO male offspring are less tolerant of high-fat diet.High-fat diet can lead to impaired glucose tolerance and arterial blood pressure in DMO male offspring;endothelial dilation function derived from resistance vessel EDHF and the smooth muscle-dependent vasodilation function mediated by exogenous CNP is impaired.