Microvascular Permeability and Sex

描述(申请人提供)：基本的微血管过程被认为是性别无关的，直到证明血流和血管张力由男性和女性不同地调节；性别是否影响交换尚不清楚，尽管它在新陈代谢和容量平衡中很重要。运动训练适应中冠状动脉交换的研究表明，基础通透性(Ps)和Ps对血管扩张剂腺苷的反应均随性别而变化。3目的是评估性激素对基础屏障特性和屏障对血管活性刺激的反应的性别差异的部分(但不是全部)贡献的假说。屏障功能将通过测量幼年(40天)和成熟(9周)、激素定义的雄性和雌性大鼠在基础和刺激条件下肌肉和肠系膜小动脉和小静脉(高代谢与低代谢)下的体积稳态、水力渗透性(Landis技术)和蛋白质渗透性(显微荧光分光光度法)等基本决定因素来量化。在AIM I中，将评估4组的基础功能，以评估性激素非依赖性的特性。由于最初的研究表明通透性反应存在性别差异，AIM II评估了腺苷和鸟苷酸环化酶途径的功能，并评估了血管磷酸二酯酶异构体(PDE I-V)的功能和分布，以确定4组患者的性别敏感信号机制。在AIM III中，急性功能将在有和没有性激素的情况下进行评估，以区分基因组和非宝石活动。将对所有动物的性激素状况进行评估，以专注于性别特有的交换变化背后的细胞和分子机制。这些关于微血管屏障动态性质的基本信息对于了解男性和女性的容量和溶质动态平衡是至关重要的，这些疾病包括健康(恢复到1g时的突触前；运动后容量减少和恢复；月经周期和怀孕)和疾病(男性休克患者的死亡率高于女性)。

DESCRIPTION (provided by applicant): Fundamental microvascular processes were assumed to be sex-independent of until it was shown that flow & vascular tone are regulated differently by men & women; whether sex influences exchange is not known in spite of its importance in metabolic and volume homeostasis. Studies of coronary exchange in adaptation to exercise training show sex-dependent changes in both basal permeability (Ps) and Ps responses to the vasodilator, adenosine. 3 Aims are proposed to evaluate the hypothesis that sex hormones contribute to some, but not all, sex-specific differences in basal barrier properties and responses of the barrier to vasoactive stimuli. Barrier function will be quantified from measures of the essential determinants of volume homeostasis, hydraulic permeability (Landis technique) and protein permeability (microspectrofluorometry) under basal and stimulated conditions in arterioles and venules of muscle and mesentery (high vs. low metabolism) from juvenile (<40 d) and mature (>9 wk), hormone-defined, male and female rats. In Aim I basal function in the 4 groups will be assessed to evaluate sex-hormone independent properties. As initial studies indicate sex-differences in permeability responses, Aim II evaluates function focusing on adenylyl and guanylyl cyclase pathways and evaluates the function and distribution of the vascular phosphodiesterase isoforms (PDE I-V) to define the sex-sensitive signaling mechanisms in the 4 groups. In Aim III acute function will be evaluated with and without sex hormones to distinguish between genomic and non-gemomic actions. Sex hormone status will be evaluated for all animals to focus on the cellular and molecular mechanisms underlying sex-specific changes in exchange. This fundamental information on the dynamic nature of the microvessel barrier is essential to understanding volume and solute homeostasis in males & females in health (pre-syncopy on return to 1g; volume loss and restoration with exercise; menstrual cycle & pregnancy) and disease (higher mortality of male than female shock patients).