Gender differences in aortic baroreceptor function and neural integration

描述（由申请人提供）：心血管功能的性别差异是众所周知的。激素和相关受体是至关重要的因素，但临床研究揭示了传入介导的自主神经系统（ANS）功能的潜在性别差异。一些心血管反射的ANS评估已被证明是两性二态的。在这项研究中，我们探讨了有关雄性和雌性大鼠主动脉压力感受器（BR）可能存在的神经解剖学、新生理和生物物理差异的假设。主动脉BR纤维类型、压力编码和神经激素调节的性别相关偏倚可能揭示了在综合心血管控制中注意到的性别差异相关的尚未被认识的机制。这一建议建立在我们之前的研究基础上，这些研究量化了有髓鞘和无髓鞘BR传入神经中离子通道的差异组成，以及这些神经解剖学上不同的传入神经通路对心率和血压的反射控制的显著不同。第一个目的是检查大鼠主动脉BR事件的性别相关差异。主动脉BR纤维的形态学分析和荧光鉴定的主动脉BR神经元（ABN）的研究提供了初步证据，表明雌性大鼠的有髓鞘BR多出约50%，首次揭示了低阈值有髓鞘ABN在功能上不同的亚型在年龄匹配的雄性中很少出现（约2%）。第二个目的量化雌二醇（E2）对这种独特亚型BR事件的神经调节能力。神经记录显示E2可增加雌鼠单髓动脉BR纤维的压力依赖性放电。生理水平的E2 （0.1 - 1 nM）至少部分通过膜结合雌激素受体作用，可选择性地增加雌性大鼠ABN亚型的兴奋性。有趣的是，E2对两性无髓鞘ABN均无影响。第三个目的是确定E2是否能以与观察到的兴奋性增加相一致的方式改变K+离子通道功能。我们的初步数据表明，与男性所有有髓鞘ABN和女性有髓鞘ABN的平衡不同，这个独特的亚群表达的BKCa通道提供了约25%的全细胞钾电流。我们进一步表明，E2选择性地抑制BKCa电流，为雌性大鼠有髓鞘BR兴奋性的E2增敏提供了一种潜在的机制。最后，在目的四中，我们确定E2是否可以改变NTS中BR传入到二阶BR神经元的单突触传递。在雄性大鼠中，髓鞘传入神经的单突触传递不涉及BKCa通道。与之形成鲜明对比的是，E2在雌性大鼠中可以增加髓鞘传入通路的单突触传递，相关研究暗示了BKCa通道的作用。从NTS的传入端到第二级BR神经元的BR感觉信息的神经整合的性别相关差异可能会导致女性人群心血管健康和疾病管理的新进展。

DESCRIPTION (provided by applicant): Gender differences in cardiovascular function are well known. Hormones and related receptors are critically important factors, but clinical studies are revealing potential gender differences in afferent mediated autonomic nervous system (ANS) function. Some ANS assessments of cardiovagal reflexes have proven to be sexually dimorphic. In this study we investigate hypotheses related to possible neuroanatomical, neuophysiological and biophysical differences between aortic baroreceptors (BR) in male and female rats. A gender-related bias in aortic BR fiber type, pressure encoding and neurohormonal regulation may reveal as yet unrecognized mechanisms associated with noted gender differences in integrated cardiovagal control. This proposal builds upon our previous studies quantifying the differential composition of ionic channels in myelinated and unmyelinated BR afferents and the manner in which this defines the strikingly different reflex control of heart rate and blood pressure evoked by these neuroanatomically distinct afferent pathways. The first aim examines gender-related differences in rat aortic BR afferents. Morphometric analysis of aortic BR fibers and study of fluorescently identified aortic BR neurons (ABN) gives preliminary evidence that female rats have ~50% more myelinated BR, revealing, for the first time, a functionally distinct subtype of low threshold myelinated ABN rarely present (~2%) in age-matched males. The second aim quantifies the neuromodulatory capacity of estradiol (E2) upon this unique subtype of BR afferents. Nerve recordings show that E2 can increase the pressure-dependent discharge of single myelinated aortic BR fibers from female rats. Physiological levels of E2 (0.1 - 1 nM) acting, at least in part, via membrane bound estrogen receptors can selectively increase the excitability of this ABN subtype in female rats. Interestingly, E2 had no effect upon unmyelinated ABN from either gender. The third aim determines if E2 can alter K+ ion channel function in a manner consistent with the observed increased excitability. Our preliminary data show that, unlike all myelinated ABN in males and the balance of myelinated ABN from females, this unique subset expresses BKCa channels that provide ~25% of the whole cell potassium current. We further show that E2 selectively inhibits this BKCa current, offering one potential mechanism for the E2 sensitization of myelinated BR excitability in female rats. Finally, in aim four we determine if E2 can alter monosynaptic transmission of BR afferents onto 2nd-order BR neurons in the NTS. In male rats, monosynaptic transmission of myelinated afferents to the NTS does not involve BKCa channels. In stark contrast, E2 in female rats can increase monosynaptic transmission of myelinated afferent pathways with companion studies implicating a role for BKCa channels. Gender-related differences in the neural integration of BR sensory information from the afferent terminal through to 2nd-order BR neurons in the NTS could potentially lead to novel advances in the management of cardiovascular health and disease in the female population. PUBLIC HEALTH RELEVANCE: Gender differences in cardiovascular function are well known and while sex hormones are important contributing factors, there is growing evidence for alternative mechanisms. This project aims to determine if there are fundamental neuroanatomical and neurophysiological differences in the baroreceptor afferent pathway between men and women. Evidence for a gender-related difference in baroreceptors could potentially lead to novel advances in the effective management of cardiovascular health and disease in the female population.