孕期咖啡因暴露诱导子代血管平滑肌功能改变与机制研究

Increasing evidence indicates that prenatal insults may increase the susceptibility to cardiovascular disease in adulthood. Caffeine, a xanthine alkaloid, widely used in form of coffee or tea, is consumed by 68-74% of pregnant women at an average intake of 125-190 mg/day. More and more attention have been paid to the effect of maternal caffeine exposure on cardiovascular functions in the adult offspring. However, there is limited information underlying the vascular mechanism. Our preliminary study found that chronic caffeine exposure in pregnancy can cause Intrauterine Growth Restriction, abnormal pressor response, enhanced constriction in mesenteric artery and increased depolarization in smooth muscle cell. These results raise the possibility that there exits impaired ion channels related to the membrane potential adjustment. Multiple approaches are to be used in our research including patch-clamp, laser confocal, synchronous dynamic monitoring of micro-arterial diameter and intravascular calcium change, etc. This project proposes that the intracellular calcium signaling and its coupling to BKCa channel underlies the imbalanced regulation of membrane potential, which therefore affect vascular tone and blood pressure. The findings may contribute to new insight to preventive or therapeutic approaches against hypertension at early developmental stages.

大量研究表明孕期不良刺激可增加子代罹患心血管病的风险。咖啡、茶、可乐等含相当量咖啡因，咖啡因可直接影响肌细胞收缩性而影响心血管功能。随着含咖啡因食品的普及，孕期咖啡因暴露对子代心血管的影响虽日益受到关注，但相关研究很少，尤其缺乏血管机制方面报道。我们前期研究发现孕期慢性咖啡因刺激可造成胎儿宫内发育迟缓，成年子代加压反应改变，肠系膜小动脉收缩功能及平滑肌细胞膜电位去极化增强，由此推测血管细胞膜电位调节相关离子通道功能可能发生改变。本课题重点用膜片钳技术，激光共聚焦，同步动态监测微动脉直径和血管细胞内钙离子实时变化技术结合分子生物学检测，探讨孕期咖啡因暴露可能诱导子代血管平滑肌细胞膜电位调节相关钙信号及其与下游BKCa通道偶联异常，致膜电位失衡，血管张力增加。研究内容有高度原创性，预期结果将为早期预防和干预胎源性高血压提供新线索和新思路，也为孕期饮食/药物相关的围产保健扩充新的理论与实用信息。

项目背景：大量研究表明孕期不良刺激可增加子代罹患心血管病的风险。咖啡、茶、可乐等含相当量咖啡因，咖啡因可直接影响肌细胞收缩性而影响心血管功能。随着含咖啡因食品的普及，孕期咖啡因暴露对子代心血管的影响虽日益受到关注，但相关研究很少，尤其缺乏血管机制方面报道。我们前期研究发现孕期慢性咖啡因刺激可造成胎儿宫内发育迟缓，成年子代加压反应改变，肠系膜小动脉收缩功能及平滑肌细胞膜电位去极化增强，由此推测血管细胞膜电位调节相关离子通道功能可能发生改变。.研究内容：本课题重点用膜片钳技术，激光共聚焦，同步动态监测微动脉直径和血管细胞内钙离子实时变化技术结结合分子生物学检测，探讨孕期咖啡因暴露可能诱导子代血管平滑肌细胞膜电位调节相关钙信号及其与下游BKCa通道偶联异常，致膜电位失衡，血管张力增加。.重要结果及数据：（1）孕期咖啡因暴露导致胎鼠宫内生长受限（IUGR）发生率显著增加；（2）孕期咖啡因暴露诱导成年子代升压反应异常，阻力血管张力增大；（3）孕期咖啡因组子代细胞膜电位去极化异常，膜电位较对照组明显升高；（4）L型钙通道电流密度及通道α1C亚基的蛋白表达水平在孕期咖啡因组显著下降；孕期咖啡因暴露可诱导胞ryanodine敏感的内钙释放功能降低。（5）孕期咖啡因暴露诱导子代肠系膜动脉平滑肌全细胞BKCa通道电流密度降低；β1亚基蛋白表达下调。.科学意义：研究内容有高度原创性，预期结果将为早期预防和干预胎源性高血压提供新线索和新思路，也为孕期饮食/药物相关的围产保健扩充新的理论与实用信息。