| Background: In pregnancy, a number of maternal physiologic or pathologic factors, including plateau-hypoxia, gestational hypertension, heart failure, anaemia, preeclampsia, pathologic and umbilical cord factors, can induce hypoxia and lead to poor intrauterine fetal growth(PIFG)because of insufficent nutrient. As an endocrine system,renin-angiotensin system (RAS), plays a role in regulating body fluid balance, cardiovascular responses, neuroendocrine activition, salt and water intake. Numbers of evidence indicated that maternal hypoxia during gestation induced changes in body fluid balance and RAS components. However, it is not clear of the effect of maternal hypoxia during gestation on the development of fetal and offsping heart, kidney, and forebrain RAS. Recent extensive studies have demonstrated that the offspring with a history of maternal hypoxia during gestation had a high incidence of cardiovascular diseases at adult stage. The increased vascular risks in the offspring were suggested to be linked to changes of renin-angiotensin system (RAS), which regulates cardiovascular and body fluid homeostasis. It is unknown whether maternal hypoxia during gestation can affect the RAS in regulation of body fluids and cardiovascular system in the offspring. Hence, this project determined the effect of maternal hypoxia during gestation on the development of RAS and"imprinting"effects in adult offspring.Part 1 Effects of maternal hypoxia during gestation on morphology and blood gas indexs in the fetusObjective: To determine the effects of the maternal hypoxia during gestation on morphology and blood gas indexs in the fetus. Methods: Food intake and body weight were measured during hypoxia gestation period(GD4-21); Fetal body weight, heart weight, kidney weight, brain weight, stem length and tail length were measured at gestation 21 day; Blood gases and electrolytes were determined with a Nova analyzer; Plasma osmolality was determined with an advanced digmatic osmometer; the renal and haunch skin blood flow were detected by a Laser Doppler. Results: Maternal hypoxia during gestation did not infulence maternal food intake and body weight, while, significantly decreased fetal body weight, heart weight, kidney and brain weight, reduced fetal stem and tail lengths, decreased plasma pO2 and SO2% level. However, others blood gas index (pH,Na+,K+,Osm,pCO2,Hb,Hct,Glu and Lac) were not changed. In addition, fetal renal and haunch skin blood flow were reduced significantly. Conclusion: Maternal hypoxia during gestation could significantly change morphologic and blood gas index in the fetus.Part 2 Effects of maternal hypoxia during gestation on body fluid homeostasis in adult offsping ratObjective: To determine the effects of maternal hypoxia during gestation on body fluid homeostasis and the RAS of kidney and forebrain in adult offspring. Methods: The adult offsprings(4-5 months, male and female) body, organ were weighted; Blood gases and electrolytes were determined with a Nova analyzer; Plasma osmolality was determined with an advanced digmatic osmometer; Water and salt intake after subcutaneous injection hypertonic saline or intracerebroventricular(i.c.v.) Ang II during 2 h period in the female and male offspring rats of two groups were measured; c-fos in the forebrain in the male offsprings of two groups were observed after i.c.v. Ang II 1 hour and the changement of AT1R and AT2R in kidney were measured with immunostaining; mRNA and protein level of AT1R and AT2R were measured with real-time PCR and western blot in forebrain and kidney of two groups both in male and female offspring. Results: The adult offspring body, other organ weights, morphologic and blood gas index did not infulenced by maternal hypoxia during gestation; Following subcutaneous injection of hypertonic saline or i.c.v. Ang II, water intake and salt appetite were all significantly increased in both male and female in two groups, water intake did not changed, however, salt appetite was significantly increased in offsping of maternal hypoxia during gestation compared to that of the control; After i.c.v. Ang II 1 hour, a significant increase of c-fos were observed in the forebrain, including PVN, SON, SFO and MnPO, not OVLT in the male offspring of maternal hypoxia during gestation; The AT1R mRNA and protein level in the forebrain of hypoxia adult offspring (female, male) were not changed, however, AT2R mRNA and protein level of those were significantly decreased; The AT1R mRNA and protein level in the kidney of hypoxia adult offspring (female, male) were significantly increased, however, AT2R mRNA and protein level of kidney in two groups were not changed. Conclusion: Maternal hypoxia during gestation significantly infulenced the body fluid equilibrium and the RAS of kidney and forebrain in adult offsping.Part 3 Effects of maternal hypoxia during gestation on cardiovascular RAS in the adult offspingObjective: To determine the effects of maternal hypoxia during gestation on cardiovascular RAS in the adult offspring. Methods: To examine blood pressure responses to intravenous injection of Angâ…¡, PD123319, losartan, or i.c.v.Angâ…¡; Contractility and relaxation of the thoracic aorta and mesenteric artery of adult offsping (female, male) in two groups were determined; Plasma Angâ… , Angâ…¡, ALD, ACTH, TXB2, ET, INS, LEP, and ANP levels were measured by radioimmunoassay; The tissue structures of the heart and thoracic aorta were determined by light microscope; The AT1R and AT2R levels in heart and thoracic aorta were examined by immunostaining. The heart mRNA and protein levels of AT1R and AT2R were measured with real-time PCR and western blot. Results: Mean arterial pressure (MAP) responses to peripheral and central AngII offspring exposed to prenatal hypoxia were not significantly stronger changed, however, the duration of the pressor effect was significantly longer than that in the control offsping, MAP responses to intravenous injection of Losartan and PD123319 were not significantly changed; In both thoracic aorta and mesenteric arteriole of the offspring exposed to prenatal hypoxia, AngII induced contraction was different from that of the control, in addition, NO, BK, and PKC channel mediated effects induced by AngII were also changed in offspring exposed to prenatal hypoxia; In addition, Plasma Angâ… , Angâ…¡,INS, ANP, ALD level were significantly decreased, while, ACTH,TXB2,and ET level were increased; The expression of AT1R and AT2R in the heart and thoracic aorta was significantly increased, while AT2R was not changed; The mRNA and protein levels of AT1R in the heart of offspring exposed to prenatal hypoxia were significantly increased compared with that in the control, while AT2R levels in the heart were significantly decreased. Conclusion: Hypoxia during pregnancy could affect the development of the RAS that in the control of the cardiovascular system. The results also indicate cardiovascular risks were increased due to fetal origin problems.
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