Microvascular Permeability and Sex

描述（由申请人提供）：基本微血管过程被认为是性别无关的，直到有研究表明男性和女性对血流和血管张力的调节不同；性别是否会影响交换尚不清楚，尽管它在代谢和体积平衡中很重要。冠状动脉交换对运动训练的适应研究显示，基底通透性（Ps）和Ps对血管扩张剂腺苷的反应都有性别依赖性的变化。目的是评估性激素在基础屏障特性和屏障对血管活性刺激的反应方面的一些（但不是全部）性别特异性差异的假设。屏障功能将通过测量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）的体积稳态、水力渗透性（Landis技术）和蛋白质渗透性（微荧光法）的基本决定因素来量化，这些条件来自幼年（<40 d）和成熟（bbb9周）、激素定义的雄性和雌性大鼠。在Aim I中，将评估4组患者的基础功能，以评估性激素独立特性。由于最初的研究表明渗透性反应存在性别差异，Aim II评估功能侧重于腺苷酸和胍基环化酶途径，并评估血管磷酸二酯酶异构体（PDE I-V）的功能和分布，以确定4组中性别敏感的信号机制。在Aim III中，急性功能将在有性激素和没有性激素的情况下进行评估，以区分基因组和非基因组作用。性激素状态将在所有动物中进行评估，以关注交换中性别特异性变化的细胞和分子机制。这些关于微血管屏障动态性质的基本信息对于理解健康男性和女性的体积和溶质内稳态（恢复1g时的晕厥前期；运动后的体积损失和恢复；月经周期和怀孕）和疾病（男性休克患者的死亡率高于女性）至关重要。

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).