神经炎症参与绝经后心血管功能中枢调节的作用机制研究

Increase in cardiovascular risks coupled with sympathetic hyperactivity is associated with a loss of estrogen in postmenopausal female. However, the mechanism responsible for postmenopasue-induced blood pressure increase and sympathetic hyperactivity has not been fully understood. The neuroinflammation in the rostral ventrolateral medulla (RVLM), a key region for control of sympathetic outflow, has been demonstrated to be a major contributor to high blood pressure and increased sympathetic outflow in cardiovascular diseases. Estrogen significantly improves cardiovascular dysfunction via repressing inflammation. Therefore, the main goal of the present project is to determine the role of RVLM neuroinflammation in mediating the cardiovascular dysfunction in postmenopause and elucidate the mechanism responsible for benificial effect of estrogen replacement treatment on postmenpause dysfunction in cardiovascular system. In animal models (ovariotomy) of postmenopause, three aims will be determined: 1) if RVLM neuroinflammtion mediates postmenopause-induced cardiovascular dysfunction; 2) if a loss of estrogen contributes to produce the neuroinflammtion in the RVLM; and 3) if estrogen replacement treatment is beneficial to cardiovascular dysfunction in postmanopause via reducing the neuroinflammtion in the RVLM. The results from this project will provide new information to expand our understanding of cardiovascular dysfunction and to search for new therapeutic strategy in postmanopause cardiovascular dysfunction.

女性绝经后以交感活动增强为特征的心血管疾病的发生率明显增加，其与雌激素水平降低密切相关，但绝经后血压升高和交感神经活动增强等心血管活动异常的具体机制并不清楚。交感中枢头端延髓腹外侧区（RVLM）神经炎症是导致血压升高和交感输出增强等心血管异常的重要机制，而且雌激素具有抑制炎症改善心血管疾病的作用。因此，本申请课题的总体目标是阐明RVLM神经炎症是否参与绝经后心血管功能的异常调节以及明确雌激素替代治疗改善绝经后心血管功能的机制。在切除卵巢造成绝经的大鼠模型上将进行三个研究内容：1）RVLM神经炎症参与绝经后心血管功能异常中的作用和意义；2）雌激素低下对RVLM神经炎症的作用和机制；3）雌激素改善绝经后心血管异常的作用以及与RVLM内神经炎症的关系。通过以上研究内容，本课题结果将为绝经后心血管功能紊乱的机制研究和防治策略提供重要的理论内容。

女性绝经后以交感活动增强为特征的心血管疾病的发生率明显增加，其与雌激素水平降低密切相关，但绝经后血压升高和交感神经活动增强等心血管活动异常的具体机制并不清楚。交感中枢头端延髓腹外侧区（RVLM）神经炎症是导致血压升高和交感输出增强等心血管异常的重要机制，而且雌激素具有抑制炎症改善心血管疾病的作用。因此，本申请课题的总体目标是阐明RVLM神经炎症是否参与绝经后心血管功能的异常调节以及明确雌激素替代治疗改善绝经后心血管功能的机制。本研究证实了：1）OVX大鼠RVLM内炎症因子水平增加以及小胶质细胞激活增多，采用米诺环素抑制小胶质细胞激活可改善绝经后大鼠心血管功能异常。2）雌激素可抑制绝经后大鼠RVLM内神经炎症，从而降低交感输出，改善绝经后大鼠心血管功能。3）OVX大鼠RVLM内PI3K通路激活可介导绝经后神经炎症，雌激素可抑制PI3K通路，减轻神经炎症，从而改善绝境后大鼠心血管功能。本研究明确了RVLM内神经炎症参与绝经后大鼠心血管功能异常，雌激素替代治疗可抑制RVLM 内PI3K通路减轻神经炎症，为绝经后大鼠心血管功能异常的机制研究和防治策略提供了新思路。