Study Of Cardiovascular Changes And Its Mechanisms In Aged Offspring Exposure To Gestational High Sucrose Diet

[Objectives] To investigate the changes of cardiovascular system and its regulation in aged offspring exposure to gestational high sucrose diet.[Methods] Pregnant rats were given standard food with 20%sucrose solution from gestational day 1- 21,its aged offsprings were high sucrose(HS) group. Pregnant rat were fed with the same food and tap water, its aged offsprings were control(Con) group. Blood electrolytes and plasma osmolarity were determined using a Nova analyzer and an advanced digmatic osmometer, respectively. Ang II concentration in plasma and vessel tissue were determined by radio-immunologic method. Blood pressure responses induced by intraventricular injection of Ang II and Losartan were assessed using femoral artery/vein cannulation. In thoracic aorta rings, dose-response effects triggered by Ang ?, Losartan+Ang II, and L-NAME+Ang ? were assessed. In mesenteric arteriole, dose-response effects induced by Ang ?, Losartan+Ang II, L-NAME+Ang ?, Nifedipine+Ang II, and Mibefradil+Ang II were assessed. In mesenteric arteriole, the responses of [Ca2+]i triggered by Ang? and Losartan+Ang II were tested using Ion Optix Ca2+ imaging system. L- and T-type calcium channel currents and their responses to Ang II and Losartan+Ang II were determined under the whole-cell model using patch clamp method. The m RNAs of AT1 a R, AT1 b R, e NOS, Cav1.2, Cav3.1, TBP, and GR in vessel tissues were semi-quantified using real-time RT-PCR. Under the application of Western Blotting, the proteins of AT1 R, e NOS, Cav1.2, Cav3.1, TBP, and GR in vessel and brain tissues were detected. The modifications of H3 Ac, H3K4me3, H3K9me3, and H3S10 ph, and the binding of TBP and GR in the promoter region of AT1 a R in the vessel tissue were determined with the method of chromatin immunoprecipitation.[Results] In the aged offspring of HS group, compared with that of control, Ang II concentration did not significantly change in plasma but significantly increased in vessel(including aorta and mesenteric arteriole) tissues. The expressions of m RNA and protein of AT1 R were significantly increased in vessel(including aorta and mesenteric arteriole). The baseline blood pressure(BP) was significantly elevated, the BP elevation responses induced by peripheral Ang II application were significantly increased, and the BP decline responses induced by peripheral Ang II application were also significantly increased. In both the aorta ring and mesenteric arteriole, the dose-response effects induced by Ang? were significantly increased and were almost abolished by Losartan. In both the aorta ring and mesenteric arteriole, the endothelial dilation effects were significantly attenuated, and the expressions of m RNA and protein of e NOS were significantly decreased. The [Ca2+]i response triggered by Ang II in mesenteric arteriole was significantly increased and almost abolished by Losartan. In the mesenteric arteriole smooth muscle cell, the whole cell L-type calcium channel current did not significantly change but T-type calcium channel current was significantly increased. The response of L-type calcium channel current to Ang II was significantly increased and almost abolished by Losartan. In the mesenteric arteriole tissue, the expressions of m RNA and protein of Cav3.1 was significantly increased but that of Cav1.2 did not change. In the promoter region of AT1 a R in the mesenteric arteriole tissue, the modification of H3 Ac, H3K4me3, and H3S10 ph were significantly increased, but that of H3K9me3 was significantly decreased. Although the expressions of m RNA and protein of TBP and GR did not change, the binding of TBP and GR in the promoter region of AT1 a R were significantly increased.[Conclusions] After the exposure of gestational high sucrose diet, the AT1R-mediated cardiovascular and its regulation was abnormally changed in the aged offspring, and was tightly associated with the alterations of epigenetics.