Essential Hypertension and Human Skin Blood Flow

原发性高血压与人体皮肤血流量

• 批准号: 7505362
• 负责人: Lacy M. ALEXANDER
• 金额: $ 38.18万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7505362
• 关键词: Age; Arginine; Arts; Attenuated; Biochemical; Biological Availability; Biopsy; Biopsy Specimen; Blood Circulation; Blood Vessels; Blood flow; Clinical; Cutaneous; Deltastab; Emotional; Enzyme Kinetics; Essential Hypertension; Financial cost; Functional disorder; 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; Smooth Muscle; Supplementation; Therapeutic Intervention; Time; United States; Up-Regulation; 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)：人体皮肤循环是一个可接近的、具有代表性的血管床，用于体内检查导致高血压(HT)血管功能障碍的机制。这一建议是我们之前工作的合乎逻辑的扩展，该工作调查了年龄和高血压相关变化在控制反射介导的皮肤血流量增加方面的血管机制。拟议的研究扩展了我们之前的研究，将最先进的体内一氧化氮(NO)特异性方法(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，以检查高血压患者皮肤血管扩张(VD)信号受损的确切信号机制。与高血压相关的血管功能障碍是多方面的，但涉及结构性一氧化氮合酶(内皮和神经元型一氧化氮合酶)的表达和活性受损以及氧化应激增加所导致的NO生物利用度的全球下降。尽管高血压患者的皮肤一氧化氮依赖型血管性痴呆明显减轻，但产生一氧化氮的一氧化氮合酶亚型的一氧化氮合成的改变仍未解决。增强的诱导型一氧化氮合酶和减弱的结构性一氧化氮合酶同工酶与高血压相关的炎症和高肾上腺素能神经血管状态有关。羟色胺抑制血管内一氧化氮合酶合成NO的可能机制包括：(1)炎症诱导诱导型一氧化氮合酶合成的NO增加，从而通过S-亚硝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-如果一氧化氮合酶底物L-精氨酸(L-精氨酸)通过精氨酸酶-优先代谢，这两者都用于限制通过组成性一氧化氮合酶合成NO-；(3)由于L-精氨酸和/或必需辅因子(四氢蝶呤(BH4))的供应不足，通过非偶联一氧化氮合酶增加氧化剂的产生。上调的精氨酸酶还通过增加L鸟氨酸介导的多胺和脯氨酸的合成，与高血压诱导的血管壁重构的发病机制有关。因此，炎症、上调的精氨酸酶、一氧化氮合酶解偶联和有害的血管壁重构与高血压有一定的联系。这项拟议的研究将配对体内和体外方法，以检查炎症、氧化应激和高血压患者皮肤血管系统中一氧化氮产生之间的可能联系。特定目标1将研究介导减弱的皮肤NO依赖的一氧化氮合酶亚型，特殊目标2将研究精氨酸酶通过结构性一氧化氮合酶调节L精氨酸合成NO的作用，特殊目标3将研究氧化应激和辅因子BH4的可获得性与一氧化氮合酶解偶联的作用。我们还将通过测量实时相对氧化剂的产生来检查上调的精氨酸酶和BH4缺乏对NOS解偶联的机制联系。公共关系：美国四分之一的人口没有被诊断出患有高血压或正在接受治疗。这一健康问题无处不在，并带来了情感、身体和经济方面的代价。这些拟议研究的结果将为高血压对皮肤的血管影响提供新的和重要的信息。此外，这些结果将为高血压血管病变的皮肤血流调节和潜在的治疗干预策略提供洞察力。