Study On The Central Mechanism Of Offspring Rat Hypertension Facilitated By Maternal High Fat Diet During Pregnancy And Lactation

Accumulating evidence indicates that maternal obesity and high fat diet(HFD)are associated with metabolic syndrome and cardiovascular diseases in adult offspring.A few studies focusing on adipose tissue imply that the mechanisms,such as the renin-angiotensin-system(RAS)and proinflammatory factors,are involved in this susceptibility to the cardiovascular diseases in adult offspring.The sympathetic nervous system(SNS)may be activated in offspring of HFD-fed dams that develop hypertension,but to date no study has shown direct evidence for the involved central sites and mechanisms underlying the transgenerational effects of maternal HFD on the prohypertensive actions in the offspring.The lamina terminalis(LT)consists of subfornical organ(SFO),median preoptic nucleus(MnPO)and organum vasculosum(OVLT).The paraventricular nucleus(PVN)is a key nucleus of the hypothalamus,consists of two parts,one is large cells area for synthesis and secretion of vasopressin and oxytocin,and the other is a small cell area for sending fibers projected directly to the brainstem and spinal cord regulation sympathetic activity,and the small cell area receives critical information from the SFO on circulating peptides,and then the PVN neurons control sympathetic nerve by the rostral ventrolateral medulla and the spinal column.LT and PVN play an important role in the long-term regulation of blood pressure and body fluid balance,LT is responsible for the perception of circulation input signals,and these signals are passed to PVN.PVN sends the signal to the spinal cord cardiovascular control center,and finally sends the signal to the periphery.SFO is a lack of blood brain barrier circumventricular organs,an interface that can directly perceive various signaling molecules in circulatory system,more importantly,SFO and PVN have direct fiber connections,PVN located in blood brain barrier involved in cardiovascular and energy regulation,so it can transfer peripheral signals about cardiovascular,body fluids,and energy state to such regulation nuclei,so as to maintain the normal function of the body.A large number of studies have confirmed that SFO and PVN are involved in the regulation of congestive heart failure,hypertension and metabolic syndrome.Therefore,the purpose of this study is to explore whether maternal HFD modulates brain RAS,oxidative stress and proinflammatory cytokines that alters angiotensin II and tumor necrosis factor-?(TNF-?)sensitivity and sensitizes angiotensin II-elicited hypertensive response in adult offspring?We used a method of high-fat diet given during pregnancy and/or lactation to propagate offspring rats.All offspring were cross-fostered by dams on the same or opposite diet to yield 4 groups: offspring of dams with CD during pregnancy and lactation(OCC),offspring of dams with HFD during lactation only(OCH),offspring of dams with HFD during pregnancy only(OHC)and offspring of dams with HFD during pregnancy and lactation(OHH).Blood pressure and heart rate were recorded by DSI telemetry system and mRNA expression in the PVN and LT(including SFO,MnPO and OVLT)was assessed in their offspring before and after systemic angiotensin II infusion so that the cardiovascular parameters and involved RAS components and inflammatory factors were determined.Further through the femoral artery and vein catheterization,in conscious state application of sodium nitroprusside and phenylephrine for detection baroreflex function,in order to evaluate the cardiovascular function.At the same time,we set up the model of cerebral ventricle intubation in the offspring of rats,intraventricular injection of Ang ? and TNF-? in conscious state,and observed the changes of blood pressure and heart rate,and then evaluated the sensitivity of animals to central stimulation.RT-qPCR analyses of In brain tissues collected from pups at 3 weeks of age,offspring from dams with HFD during either pregnancy,lactation or both exhibited increased mRNA expression of RAS components(AGT and ACE1 in the LT and AT1 R in the PVN),NADPH oxidase(NOX2 in the LT)and the proinflammatory cytokines(TNF-? in both the LT and PVN)when compared with offspring of dams fed control diet during pregnancy and lactation.10 weaks of ages,HFD feeding during either pregnancy,lactation or both resulted in significant decreases in slope values for bradycardia in the offspring(OHC,OCH and OHH)when compared to offspring of dams with control diet during both pregnancy and lactation.In contrast,the slope values for tachycardia in OCH and OHH were significantly depressed,but not in OHC.Icv ANG II treatment elicited an augmented pressor response in both the OCH and OHH when compared to the OCC,but not to the OHC.Icv ANG II administration induced comparable,but not significant decreases in HR in all groups.Meanwhile,in offspring of dams fed HFD in either period including the OHC,OCH and OHH,icv TNF-? treatment elicited an augmented pressor responses when compared to the OCC with TNF-? administration.Icv TNF-? administration induced slight but significant increases in HR in all groups,However,in offspring of dams fed HFD in either period including the OHC,OCH and OHH,icv TNF-? treatment elicited an augmented tachycardic responses when compared to the OCC.During infusion of the slow pressor dose of ANG II,the offspring of dams fed HFD during either pregnancy,lactation or both showed a significantly enhanced hypertensive response(OHC,21.3±3.9;OCH,25.0±3.8;OHH,29.7±2.9 mmHg)compared with the male offspring of control diet fed dams(OCC,13.1±2.4 mmHg).ANG II administration did not induce significant changes in HR in all groups.In LT tissues,the slow-pressor ANG II infusion resulted in a significant increase in mRNA expression of RAS components(renin,AGT,ACE1 and AT1R),NADPH oxidase(NOX2)and proinflammatory cytokines(TNF-? and IL-6,but except IL-1?)in the group of OCC when compared with the OCC with saline.Compared with the OCC treated with ANG II,the offspring of dams fed HFD exhibited enhanced expression of some of RAS components and proinflammatory cytokines,which included the expression of TNF-? and IL-1? in the OHC,and the expression of renin,ACE1,TNF-? and IL-1? in both the OCH and OHH after ANG II treatment.Furthermore,the expression of renin and ACE1 in both the OCH and OHH and the expression of IL-6 and IL-1? in the OHH were greater than that in the OHC after ANG II treatment.In PVN tissues,ANG II infusion elicited a significant increase in the mRNA expression of NOX2,TNF-?,IL-6 and IL-1? in the OCC when compared with the OCC with saline.The mRNA expression of renin,AGT,ACE1 and AT1 R was not higher after ANG II.All of offspring of HFD fed dams showed enhanced mRNA expression of NOX2,IL-1? and IL-6 after ANG II treatment.Furthermore,the expression of NOX2 in both the OCH and OHH was greater than that in the OHC.In a word,these offspring also showed a decreased baroreflex sensitivity and an elevated pressor response to intracerebroventricular microinjection of either angiotensin II or TNF-?.Furthermore,chronic systemic infusion of angiotensin II resulted in enhanced upregulation of mRNA expression of RAS components,NADPH oxidase and proinflammatory cytokines in the LT and PVN and an augmented hypertensive response in the OHC,OCH and OHH when compared to the OCC.The research suggests that maternal rat HFD during pregnancy and/or lactation blunts baroreflex sensitivity function and enhances pressor responses to angiotensin II or proinflammaroty cytokines,and that upregulation of the brain RAS,oxidative stress and proinflammatory cytokines in these offspring may contribute to maternal HFD-induced sensitization of the hypertensive response to angiotensin II.