妊娠不同时期缺氧对雄性子代大鼠成年期心肌重构的影响

Influence of hypoxia during different pregnancy stages on myocardial remodeling in adult offspring rats

目的 研究妊娠不同时期缺氧对雄性子代大鼠成年期心肌重构的影响. 方法 将24只Sprague Dawley孕鼠随机分为早期缺氧组、中期缺氧组、晚期缺氧组和空白对照组,每组6只.缺氧组孕鼠分别自妊娠第3、9或1 5天起,每日置于氧气浓度为（10±1）％的低氧舱3h,至自然分娩.各组雄性子代大鼠于3和5月龄时检测血压、左心室质量指数（左心室质量/体重）、心肌纤维直径,以及心肌Ⅰ型和Ⅲ型胶原蛋白表达情况.采用单因素方差分析和SNK检验进行统计学分析. 结果 早期缺氧组子代大鼠3和5月龄收缩压明显升高,与同月龄空白对照组比较,差异有统计学意义[3月龄：（122.0±11.7） mmHg与（108.3±9.5） mmHg,F=2.97;5月龄：（128.5±7.9） mmHg与（114.6±10.0） mmHg,F=3.17;P值均＜0.05;1 mmHg=0.133 kPa].3月龄时,中期缺氧组子代大鼠的心脏质量指数和左心室质量指数升高,与空白对照组比较,差异有统计学意义[心脏质量指数：2.92±0.06与2.67±0.06,左心室质量指数：2.15±0.05与1.98±0.02,P值均＜0.05].5月龄时,早、中期缺氧组的心脏质量指数、左心室质量指数明显高于空白对照组[心脏质量指数：2.68±0.05和2.64±0.06与2.39±0.30,左心室质量指数：1.99±0.03和1.96±0.05与1.80±0.02],差异有统计学意义（P值均＜0.05）.3和5月龄雄性子代大鼠心肌组织HE染色切片光镜下见心肌细胞结构清晰,排列规整,各组间心肌纤维直径差异无统计学意义.3月龄时,中期缺氧组与空白对照组比较,心肌组织Ⅰ型和Ⅲ型胶原蛋白相对表达量增加[Ⅰ型胶原蛋白：0.98±0.02与0.87±0.02;Ⅲ型胶原蛋白：0.87±0.01与0.82±0.01;P值均＜0.05],中期缺氧组Ⅲ型胶原蛋白相对表达量也较晚期缺氧组（0.79±0.02）增加,差异有统计学意义（P＜0.01）.5月龄时,早期缺氧组心肌组织Ⅰ型和Ⅲ型胶原蛋白的相对表达量明显高于空白对照组（Ⅰ型胶原：1.76±0.07与0.48±0.04;Ⅲ型胶原：0.68±0.05与0.34±0.03;P值均＜0.01）,且明显高于晚期缺氧组（Ⅰ型和Ⅲ型胶原分别为0.63±0.07和0.41±0.03）,差异有统计学意义（P值均＜0.01）.中期缺氧组心肌组织Ⅰ型和Ⅲ型胶原蛋白的相对表达量（分别为1.61±0.05和0.61±0.04）明显高于空白对照组和晚期缺氧组,差异有统计学意义（P值均＜0.01）. 结论 妊娠不同时期缺氧对雄性子代大鼠成年期心脏组织具有不同的影响.妊娠早、中期开始缺氧会引起子代心脏胶原沉积,而不出现心肌细胞肥大,且心脏胶原沉积可能独立于血压改变.

Objective To evaluate whether the timing of maternal hypoxia during pregnancy could myocardial remodeling in adult offspring.Methods Twenty-four pregnant rats were assigned to the maternal hypoxia group starting from the early period of pregnancy （G1,day 3 to 21 of pregnancy）,the group starting from the middle period of pregnancy （G2,day 9 to 21 of pregnancy）,the group starting from the late period of pregnancy （G3,day 15 to 21 of pregnancy）,or the control group （G0）.Six rats were included in each group.Rats in the maternal hypoxia groups （G1,G2 and G3） were subjected to hypoxia for 3 hours in a low pressure cabin with an oxygen concentration of （10± 1） ％.Systolic blood pressure,wet weight of the left ventricle normalized for body weight （left ventricular weight/body weight,LVW/BW）,diameter of cardiomyocytes,and the expression levels of collagen Ⅰ and collagen Ⅲ were measured in adult male offspring at the age of 3 and 5 months.One-way ANOVA and SNK test were used for statistical analysis.Results Maternal hypoxia from day 3 to 21 of pregnancy induced higher systolic blood pressure in male offspring at the age of 3 months and 5 months [3 months：G1 （122.0± 11.7） mmHg,G0 （108.3±9.5） mmHg,F=2.97; 5 months：G1 （128.5±7.9） mmHg,G0 （114.6±-10.0） mmHg,F=3.17,both P＜0.05].Maternal hypoxia also led to a higher LVW/BW ratio （G1 1.99±0.03,G0 1.80±0.02,P＜0.05）,and increased collagen Ⅰ and collagen Ⅲ expression （collagen Ⅰ /β-actin：G1 1.76±0.07,G0 0.48±0.04,P＜0.01; collagen Ⅲ /β-actin：G1 0.68±0.05,G0 0.34±0.03,P＜0.01） in adult male offspring at the age of 5 months.Maternal hypoxia from day 9 to 21 of pregnancy induced a higher LVW/BW ratio （3 months：G2 2.15 ± 0.05,G0 1.98 ± 0.02,P＜0.05; 5 months：G2 1.96±±0.05,G0 1.80±0.02,P＜0.05）,and increased collagen Ⅰ and collagen Ⅲ expression （3 months：collagen Ⅰ /β-actin G2 0.98±±0.02,G0 0.87±0.02,P＜0.05; collagen Ⅲ /β-actin：G2 0.87±±0.01,G0 0.82±0.01,P＜0.05; 5 months; collagen Ⅰ /β-actin G2 1.61±0.05,G0 0.48±0.04,P＜0.01; collagen Ⅲ / β-actin：G2 0.61 ±0.04,G0 0.34±0.03,P＜0.01） in male offspring at the age of 3 months and 5 months,but did not affect systolic blood pressure.Maternal hypoxia from day 15 to 2l did not have any effect.The diameter of cardiomyocytes in male offspring was not significantly different between the groups.Conclusions Maternal hypoxia during different periods of pregnancy has different effects on cardiac structure in adult rat offspring.Maternal hypoxia started in early or mid-pregnancy leads to cardiac collagen deposition without an increase in myocyte size in adult offspring,which may be independent of the change in blood pressure.