Molecular Mechanisms of Hypertension in the Microcirculation

描述（由申请人提供）：血管紧张素II（Ang II）在高血压的血管肥大和内皮功能障碍的病理生理学中起着重要作用，然而，关于导致高血压中这种血管改变的细胞或分子机制知之甚少。Toll样受体（TLR）是I型跨膜受体，其在先天免疫中起关键作用。最近的证据表明，除了LPS之外，TLR 4信号传导可以被细胞应激和/或损伤期间产生的内源性因子激活。我们的初步数据表明，TLR 4缺乏限制了血管紧张素II诱导的内皮功能障碍的发展。哺乳动物雷帕霉素靶蛋白（mTOR，phosphoinositide 3-kinase-related kinase family of protein kinases）是近年来发现的一种重要的细胞生长和肥大调节因子。虽然mTOR在细胞生长和肥大中起重要作用，但mTOR在高血压中的作用尚未被研究。本实验室的前期研究表明，白细胞介素（IL）-6和NAD（P）H氧化酶在血管紧张素II依赖性高血压相关的内皮功能障碍和血管肥大中起重要作用。我们的总体假设是，TLR 4和mTOR是关键的分子机制，相对维斯IL-6和Nox衍生的超氧化物，有助于高血压和高血压相关的血管和微血管后遗症。三个具体目标将被解决：目标1将测试的假设，TLR 4激活是一个初始事件，有助于血管紧张素II依赖性高血压的血管肥大和内皮功能障碍。目的2将检验以下假设：在Ang II依赖性高血压中，TLR 4激活下游的mTOR激活有助于血管肥大和内皮功能障碍。目的3将验证IL-6和NAD（P）H氧化酶衍生的超氧化物在Ang II依赖性高血压中充当TLR 4活化和mTOR下游活化之间的分子联系的假设。所提出的研究是非常新颖和非常重要的，因为它们代表了TLR 4和mTOR信号传导在与人类高血压临床相关的血管和微血管改变中的作用的第一个机制检查。这些研究在高血压中也具有重要的转化意义，因为它们将确定新的分子靶点用于治疗干预。

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) plays a central role in the pathophysiology of vascular hypertrophy and endothelial dysfunction in hypertension, however very little is known regarding the cellular or molecular mechanisms that contribute to such vascular alterations in hypertension. Toll-like receptors (TLR) are type I transmembrane receptors that play a key role in innate immunity. Recent evidence suggests that, in addition to LPS, TLR4 signaling can be activated by endogenous factors produced during cell stress and/or injury. Our preliminary data indicate that TLR4 deficiency limits the development of Ang II-induced endothelial dysfunction. The mammalian target of rapamycin (mTOR; a member of the phosphoinositide 3-kinase-related kinase family of protein kinases) has recently been identified as an important regulator of cell growth and hypertrophy. Although mTOR has been implicated as playing an important role in cell growth and hypertrophy, the role of mTOR has not been previously examined in hypertension. Previous studies from our laboratory have implicated an important role for interleukin (IL)-6 and NAD(P)H oxidase in the endothelial dysfunction and vascular hypertrophy associated with Ang II-dependent hypertension. Our overarching hypothesis is that TLR4 and mTOR are key molecular mechanisms, vis-a-vis IL-6 and Nox-derived superoxide, that contribute to hypertension and hypertension-related vascular and microvascular sequelae. Three Specific Aims will be addressed: Aim 1 will test the hypothesis that TLR4 activation is an initial event that contributes to vascular hypertrophy and endothelial dysfunction in Ang II-dependent hypertension. Aim 2 will test the hypothesis that mTOR activation downstream of TLR4 activation contributes to vascular hypertrophy and endothelial dysfunction in Ang II-dependent hypertension. Aim 3 will test the hypothesis that IL-6 and NAD(P)H oxidase-derived superoxide serves as molecular links between TLR4 activation and downstream activation of mTOR in Ang II- dependent hypertension. The proposed studies are extremely novel and highly significant as they represent the first mechanistic examination of the roles of TLR4 and mTOR signaling in vascular and microvascular alterations that are clinically relevant to human hypertension. The studies also hold translational importance in hypertension as they will identify new molecular targets for therapeutic intervention.