Microvascular Permeability and Sex

描述（由申请人提供）：基本的微血管过程被认为是性别无关的，直到显示出男性和女性对血流和血管张力的调节不同;尽管性别在代谢和体积稳态中很重要，但性别是否影响交换尚不清楚。对运动训练适应性冠状动脉交换的研究表明，基础渗透性（Ps）和Ps对血管扩张剂腺苷的反应均存在性别依赖性变化。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某些（但不是全部）性别特异性差异的假设。屏障功能将通过测量幼年（<40 d）和成熟（>9 wk）、雄性和雌性大鼠肌肉和肠系膜（高代谢vs.低代谢）的小动脉和小静脉中基础和刺激条件下的体积稳态、液压渗透性（Landis技术）和蛋白质渗透性（显微荧光光谱法）的基本决定因素来量化。在目的I中，将评估4组的基础功能，以评价性激素非依赖性特性。由于初步研究表明渗透性反应存在性别差异，因此Aim II评价了腺苷酸和鸟苷酸环化酶途径的功能，并评价了血管磷酸二酯酶亚型（PDE I-V）的功能和分布，以确定4组中的性别敏感性信号传导机制。在目的III中，将在有和没有性激素的情况下评价急性功能，以区分基因组和非基因组作用。将评价所有动物的性激素状态，重点关注交换中性别特异性变化的细胞和分子机制。关于微血管屏障的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稳态（恢复到1g的前晕厥;运动的体积损失和恢复;月经周期和怀孕）和疾病（男性休克患者的死亡率高于女性休克患者）是必不可少的。

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).