Age and Control of Human Skin Flow

描述(申请人提供)：65岁以上的人对与寒冷和炎热有关的疾病和死亡的贡献不成比例，在寒冷和炎热的天气中，各种原因造成的死亡的相对风险增加。由于老年人在即使是温和的加热或降温(即没有颤抖或出汗)期间核心温度漂移更大，血管运动调节改变是与年龄相关的重大缺陷。最近我们研究了与年龄相关的反射减弱的皮肤血管收缩(VC)和血管扩张(VD)的机制。老年皮肤的这种反射性皮肤血管反应性减弱是由于肾上腺素能VC和活性胆碱能VD协同递质(S)的功能丧失，以及下游血管信号的改变，包括(1)肾上腺素能脱敏，(2)一氧化氮(NO)可获得性降低。这项工作的合乎逻辑的扩展，由挑衅性的初步和试点数据支持，是检查氧化剂诱导的四氢生物蝶呤(BH4)生物利用度降低在衰老皮肤血管系统中的作用。人类衰老与氧化应激增加有关，导致关键的酶辅助因子BH4被破坏。BH4在神经和血管组织中普遍存在，并已成为一个有效的分子靶点，可能是减弱反射皮肤VC和VD机制的基础。BH4中与年龄相关的缺陷似乎在减弱的反射性皮肤VC中起着核心作用。在肾上腺素能神经末梢，BH4是合成和包装儿茶酚胺所必需的，因为它是酪氨酸羟基酶的关键辅助因子，并保持酶的还原活性形式。在具体目标1中，我们将在不同的实验中使用生理和药物刺激来检测BH4生物利用度降低在老年皮肤减弱的反射性VC中的作用，以诱导交感VC。BH4也是一氧化氮合酶(NOS)亚型的重要辅助因子，而一氧化氮合酶(NOS)亚型是反射性皮肤VD充分表达所必需的。在底物和/或氧化剂诱导的BH4缺乏过程中，NOS解偶联，从而导致超氧化物的产生。增加一氧化氮合酶的底物利用率和/或提供超生理学剂量的抗坏血酸可增加老年人皮肤中的一氧化氮依赖型血管性痴呆。由于底物的可获得性在一氧化氮合酶解偶联中的假定作用，以及抗坏血酸作为(1)非特异性抗氧化剂、(2)S精氨酸酶亚硝化的抑制剂和(3)BH4的化学稳定剂/再合成剂的作用机制的冗余，我们现在的目的是探讨BH4缺乏在老年人皮肤一氧化氮合酶解偶联中的作用。在特定的目标2中，我们将确定BH4和底物可获得性降低在一氧化氮合酶解偶联中的作用，该解偶联导致老年皮肤中NO依赖的反射性皮肤血管性痴呆减弱。在具体目标3中，我们将测试系统口服BH4补充策略在改善老年受试者在热应激(全身降温和加热；在单独的实验中)期间反射性皮肤VC和VD方面的效果。与公共健康相关：随着更大比例的人口超过退休年龄，老年人的健康问题变得无处不在，造成高昂的情感、身体和经济成本。这项研究的结果将为老年人导致热损伤和死亡的血管收缩和血管扩张受损的生理学提供新的重要信息。此外，这些研究的结果可能提供一种口服干预策略，从功能上改善老年人在热应激期间受损的皮肤血管反应性。

DESCRIPTION (provided by applicant): Humans over the age of 65 contribute disproportionately to cold- and heat-related morbidities and mortalities and the relative risk of death from all causes increases during cold and hot weather. Because core temperature excursions during even mild heating or cooling (i.e., in the absence of shivering or sweating) are greater in the elderly, altered vasomotor regulation is the seminal age-related deficit. Recently we have examined the mechanisms of age-related attenuated reflex cutaneous vasoconstriction (VC) and vasodilation (VD). This attenuated reflex cutaneous vasoreactivity in aged skin is due to a functional loss of adrenergic VC and active cholinergic VD co-transmitter(s), and altered downstream vascular signaling including (1) adrenergic desensitization, and (2) decreased nitric oxide (NO) availability. The logical extension of that work, supported by provocative preliminary and pilot data, is to examine the role of oxidant-induced reduced tetrahydrobiopterin (BH4) bioavailability in the aged cutaneous vasculature. Human aging is associated with increased in oxidant stress leading to the destruction of the critical enzymatic cofactor BH4. BH4 is ubiquitous throughout neural and vascular tissues and has emerged as a viable molecular target that may underlie both attenuated reflex cutaneous VC and VD mechanisms. Age-related deficiencies in BH4 appear to play a central role in attenuated reflex cutaneous VC. In adrenergic nerve terminals, BH4 is required for the synthesis and packaging of catecholamines by serving as a critical cofactor for tyrosine hydroxylase and by maintaining the enzyme in its reduced active form. In Specific Aim 1 we will examine the role of reduced BH4 bioavailability in attenuated reflex VC in aged skin using physiological and pharmacological stimuli in separate experiments to induce sympathetic VC. BH4 is also an essential cofactor for the NO-synthase (NOS) isoforms which are necessary for the full expression of reflex cutaneous VD. NOS uncouples during substrate and/or oxidant-induced BH4 deficiencies resulting in superoxide production. Increasing substrate availability for NOS and/or providing supraphysiological doses of ascorbate augments NO-dependent VD in aged human skin. Because of the putative role of substrate availability in NOS uncoupling, and the redundancies in the mechanisms of action of ascorbate as (1) a non-specific antioxidant, (2) an inhibitor of S-nitrosylation of arginase, and (3) a chemical stabilizer/resynthesizer of BH4, we now aim to explore the role of BH4 deficiency in NOS uncoupling in aged human skin. In Specific Aim 2 we will determine the roles of BH4 and reduced substrate availability in the NOS uncoupling that results in attenuated NO-dependent reflex cutaneous VD in aged skin. In Specific Aim 3 we will test the efficacy of systemic oral BH4 supplementation strategies in improving reflex cutaneous VC and VD in aged human subjects during thermal stress (whole body cooling and heating; in separate experiments). PUBLIC HEALTH RELEVANCE: As a larger percent of the population surpasses retirement-age, the health issues of the elderly become pervasive exacting emotional, physical and financial costs. The results from this study will provide new and important information on the physiology governing impaired vasoconstriction and vasodilation in older humans that leads to thermal injury and death. Furthermore, results from these studies may provide an oral intervention strategy to functionally improve impaired cutaneous vasoreactivity in the aged during thermal stress.