Essential Hypertension & Human Skin Blood Flow

原发性高血压

• 批准号: 8596842
• 负责人: Lacy M. ALEXANDER
• 金额: $ 34.93万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-08-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596842
• 关键词: Age; Arginine; Attenuated; Biochemical; Biological Availability; Biopsy; Biopsy Specimen; Blood Circulation; Blood Vessels; Blood flow; Clinical; Cutaneous; Deltastab; Emotional; Enzyme Kinetics; Essential Hypertension; Financial cost; Gene Expression; Generations; Health; Heating; Human; Hypertension; Impairment; In Vitro; Inflammation; Inflammatory; Intervention; Investigation; Isoenzymes; Link; Measures; Mediating; Metabolism; Methodology; Microdialysis; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Ornithine; Oxidants; Oxidative Stress; Pathogenesis; Pathology; Polyamines; Population; Production; Proline; Protein Isoforms; Reflex control; Regulation; Relative (related person); Research; Role; Sampling; Signal Transduction; Signaling Molecule; Skin; Supplementation; Therapeutic Intervention; Time; United States; Up-Regulation; Vascular Diseases; Vascular remodeling; Vasodilation; Work; arginase; cofactor; hemodynamics; human NOS3 protein; human subject; in vivo; inhibitor/antagonist; insight; muscle hypertrophy; oxidant stress; response; tetrahydrobiopterin; thermal stress; vascular bed

DESCRIPTION (provided by applicant): The human cutaneous circulation is an accessible, representative vascular bed for in vivo examination of mechanisms that contribute to vascular dysfunction with essential hypertension (HT). This proposal is a logical extension of our previous work investigating the vascular mechanisms underlying age and hypertensive-related changes in the control of reflex-mediated increases in skin blood flow. The proposed studies expand our previous research by pairing state-of-the-art nitric oxide (NO) specific in vivo methodologies (local heating and intradermal microdialysis) with in vitro analysis of human skin samples to examine the precise signaling mechanisms underlying impaired cutaneous vasodilatory (VD) signaling in humans with HT. Vascular dysfunction associated with HT is multifaceted but involves global decreases in NO bioavailability induced by impairments in constitutive NO-synthases (endothelial and neuronal NOS) expression and activity as well as increased oxidant stress. Although, cutaneous NO-dependent VD is clearly attenuated in hypertensive humans alterations in NO synthesis from the NOS isoforms producing NO are unresolved. Augmented inducible NOS and attenuated constitutive NOS isozymes are implicated in the inflammatory and hyperadrenergic neurovascular state associated with HT. Putative HT-induced mechanisms decreasing NO synthesis from the constitutive NOSs in the vasculature include (1) an inflammatory-induced increase in iNOS- synthesized NO which changes arginase enzyme kinetics (decreased Km) through S-nitrosylation, (2) a hemodynamic-induced upregulation of arginase-- both of which serve to limit NO synthesis through constitutive NOSs due to preferential metabolism if the NOS substrate L-arginine (L-arg) by arginase-- and (3) an increase in oxidant production through uncoupled NOS due to inadequate L-arg and/or essential cofactor (tetrahydriobiopterin (BH4)) availability. Upregulated arginase is also linked to the pathogenesis of hypertension-induced vessel wall remodeling through increased L-ornithine-mediated polyamine and proline synthesis. Thus, there is a mechanism linking inflammation, upregulated arginase, NOS uncoupling and deleterious vessel wall remodeling with HT. The proposed investigation will pair in vivo and in vitro methodologies to examine the putative link between inflammation, oxidant stress, and NO production in the cutaneous vasculature of humans with HT. Specific Aim 1 will examine the NOS isoforms mediating attenuated cutaneous NO-dependent, Specific Aim 2 will examine the role of arginase in regulating L-arginine availability for NO synthesis through the constitutive NOSs, and Specific Aim 3 will examine roles of oxidative stress and cofactor BH4 availability as they relate to NOS uncoupling. We will also examine the mechanistic link between upregulated arginase and BH4 deficiency on NOS uncoupling by measuring real time relative oxidant production. PUBLIC RELEVANCE: One quarter of the population in the United States has undiagnosed or is being treated for essential hypertension. This health issue is pervasive and exacts emotional, physical, and financial costs. The results from these proposed studies will provide new and important information on the vascular effects of hypertension in the skin. Further, these results will provide insight into the regulation of skin blood flow and potential therapeutic intervention strategies for hypertensive vascular pathology.

描述（由申请人提供）：人体皮肤循环是一种可接近的、有代表性的血管床，用于体内检查导致原发性高血压（HT）血管功能障碍的机制。这一提议是我们之前研究年龄和高血压相关变化的血管机制的工作的逻辑延伸，以控制反射介导的皮肤血流增加。拟议的研究将最先进的一氧化氮 (NO) 特异性体内方法（局部加热和皮内微透析）与人体皮肤样本的体外分析相结合，以检查皮肤血管舒张受损背后的精确信号机制，从而扩展了我们之前的研究。 (VD) 人类 HT 信号传导。与 HT 相关的血管功能障碍是多方面的，但涉及由组成型 NO 合成酶（内皮和神经元 NOS）表达和活性受损以及氧化应激增加引起的 NO 生物利用度整体下降。尽管皮肤NO依赖性VD在高血压人群中明显减弱，但从产生NO的NOS亚型合成NO的改变尚未解决。增强的诱导型 NOS 和减弱的组成型 NOS 同工酶与 HT 相关的炎症和高肾上腺素神经血管状态有关。假定的 HT 诱导的减少脉管系统中组成型 NOS 合成 NO 的机制包括 (1) 炎症诱导的 iNOS 合成 NO 增加，通过 S-亚硝基化改变精氨酸酶动力学（Km 降低），(2) 血流动力学诱导的精氨酸酶上调——如果 NOS 底物 L-精氨酸优先代谢，这两者都会限制通过组成型 NOS 的 NO 合成(L-arg) 通过精氨酸酶 - 和 (3) 由于 L-arg 和/或必需辅因子（四氢生物蝶呤 (BH4)）可用性不足，通过未偶联的 NOS 增加氧化剂产量。精氨酸酶上调还通过增加 L-鸟氨酸介导的多胺和脯氨酸合成与高血压诱导的血管壁重塑的发病机制有关。因此，存在一种将炎症、精氨酸酶上调、NOS 解偶联和有害血管壁重塑与 HT 联系起来的机制。拟议的研究将结合体内和体外方法来检查 HT 患者皮肤血管系统中炎症、氧化应激和 NO 产生之间的假定联系。具体目标 1 将检查介导减弱的皮肤 NO 依赖性的 NOS 亚型，具体目标 2 将检查精氨酸酶在调节 L-精氨酸通过组成型 NOS 合成 NO 的可用性中的作用，具体目标 3 将检查氧化应激和辅因子的作用BH4 可用性，因为它们与 NOS 解偶联有关。我们还将通过测量实时相对氧化剂产生来研究精氨酸酶上调和 BH4 缺乏对 NOS 解偶联之间的机制联系。公众相关性：美国四分之一的人口未确诊原发性高血压或正在接受原发性高血压治疗。这一健康问题普遍存在，并造成情感、身体和经济损失。这些拟议研究的结果将为高血压对皮肤血管的影响提供新的重要信息。此外，这些结果还将深入了解皮肤血流的调节和高血压血管病理学的潜在治疗干预策略。