Targeting the Endothelial Glycocalyx to Enhance Vascular Function and Exercise-Induced Vascular Adaptations in Type 2 Diabetes

靶向内皮糖萼以增强 2 型糖尿病的血管功能和运动诱发的血管适应

• 批准号: 10363914
• 负责人: Camila Margarita Manrique Acevedo
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363914
• 关键词: Adjuvant; Adult; Arteries; Biochemical; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Characteristics; Charge; Chronic; Clinical Trials; Diabetes Mellitus; Diagnosis; Dietary Supplementation; Double-Blind Method; Endothelium; Epidemic; Exercise; Exhibits; Exposure to; Glucosamine Sulfate; Glycocalyx; Glycoproteins; Hyaluronan; Impairment; Individual; Inflammation; Left; Life Style Modification; Mediating; Methodology; Molecular Weight; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Patients; Phase; Physical activity; Placebos; Population; Prevalence; Proteoglycan; Randomized; Research; Role; Side; Signal Transduction; Stimulus; Structure; Superoxide Dismutase; Supplementation; Testing; Therapeutic; Thick; Veterans; db/db mouse; design; diabetic; exercise training; fucoidan; hemodynamics; improved; lifestyle intervention; mechanical force; mechanotransduction; military veteran; mortality; mouse model; novel; prevent; prospective; randomized placebo controlled trial; restoration; shear stress

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in Veterans with type 2 diabetes (T2D). Lifestyle modifications, including increased physical activity, are recommended as first-line therapy for the management of T2D. Unfortunately, the efficacy of these lifestyle interventions for preventing CVD morbidity and mortality in patients with T2D is not well-established. Available evidence from our group and others indicates that vascular adaptations to exercise training are impaired in subjects with T2D. We propose that diminished vascular adaptations explain why increased physical activity does not lead to a robust reduction in CVD morbidity and mortality in T2D. However, the mechanisms responsible for this deficit in vascular adaptations to exercise in T2D remain unknown. This is a major limitation for identifying new adjuvant therapeutics to maximize the cardiovascular benefits of exercise in the diabetic population. Exercise exerts direct effects on the vasculature via repetitive exposure to hemodynamic stimuli or shear stress. The increased blood flow and luminal shear stress attendant to each bout of exercise are primary mechanisms contributing to vascular adaptations. Shear stress is detected by mechanosensitive endothelial luminal structures, such as the glycocalyx, that convert mechanical forces into biochemical signals via mechanotransduction. As such, we propose that an intact endothelial glycocalyx is required for the mechanotransduction of increased shear stress and the subsequent chronic vascular adaptations associated with exercise to occur. Notably, glycocalyx degradation is a classic feature of T2D. Accordingly, our overarching hypothesis is that endothelial glycocalyx degradation is a key factor precluding shear stress mechanotransduction and consequent exercise-induced vascular adaptations in T2D. The corollary to this hypothesis is that restoration of the endothelial glycocalyx by dietary supplementation of glycocalyx precursors (DSGP) will improve vascular adaptations to exercise in T2D. Specifically, in Aim 1 (Proof of Concept Clinical Trial Phase), we will document that DSGP enhances endothelial glycocalyx integrity in patients with T2D. Although we provide preliminary evidence that DSGP can increase glycocalyx thickness and endothelial function in a mouse model of T2D, this will be the first study to demonstrate these effects in T2D subjects. The effects of DSGP for eight weeks will be studied using a double-blinded randomized placebo control trial. Subsequently, in Aim 2 (Expended Clinical Trial Phase), we will demonstrate the permissive role of the endothelial glycocalyx in exercise-induced vascular adaptations in patients with T2D. Having shown that restoration of the endothelial glycocalyx via DSGP is feasible in T2D subjects, we will now investigate whether such supplementation will potentiate exercise training-induced improvements in endothelial function. This will be accomplished in a factorial balanced design in which T2D subjects will be randomized to DSGP or placebo with and without concurrent exercise training for eight weeks. Our team is poised to move cardiovascular and diabetes research forward with a translational project that will exert a sustained, powerful impact across a number of levels of inquiry that are novel conceptually, methodologically, and therapeutically. Indeed, targeting the glycocalyx holds extraordinary promise for achieving optimal exercise-induced vascular adaptations in Veterans with T2D, thus maximizing the cardiovascular benefits of exercise.

项目总结/摘要 心血管疾病（CVD）是2型糖尿病（T2 D）退伍军人死亡的主要原因。 生活方式的改变，包括增加体力活动，被推荐作为一线治疗。 T2 D管理不幸的是，这些生活方式干预预防CVD发病率的有效性 T2 D患者的死亡率尚未得到充分证实。我们小组和其他人提供的证据 表明血管对运动训练的适应性在患有T2 D的受试者中受损。我们建议 血管适应性减弱解释了为什么增加体力活动不会导致 2型糖尿病患者的CVD发病率和死亡率。然而，造成这种血管缺陷的机制， 2型糖尿病患者的运动适应性尚不清楚。这是鉴定新佐剂的主要限制 治疗，以最大限度地提高糖尿病人群运动的心血管益处。锻炼使 通过反复暴露于血液动力学刺激或剪切应力对血管系统产生直接影响。的 增加的血流量和腔剪切应力伴随着每一回合的运动是主要的机制 有助于血管适应。剪切应力通过机械敏感的内皮管腔检测。 结构，如糖萼，通过将机械力转化为生化信号， 机械传导因此，我们认为，完整的内皮糖萼是需要的， 增加的剪切应力和随后的慢性血管适应性相关的机械转导 有了锻炼才能发生。值得注意的是，糖萼降解是T2 D的典型特征。因此，我们的 总体假设是内皮糖萼降解是排除剪切应力的关键因素 T2 D中的机械传导和随后的运动诱导的血管适应。由此推论 假设是通过饮食补充糖萼前体来恢复内皮糖萼 （DSGP）将改善T2 D患者对运动的血管适应。具体而言，在目标1（临床概念验证 试验阶段），我们将记录DSGP增强T2 D患者的内皮糖萼完整性。 虽然我们提供了初步证据表明DSGP可以增加糖萼厚度和内皮细胞 在T2 D小鼠模型中发挥作用，这将是第一项证明T2 D受试者中这些作用的研究。的 将使用双盲随机安慰剂对照试验来研究DSGP八周的效果。 随后，在目标2（扩展临床试验阶段）中，我们将证明 内皮糖萼在2型糖尿病患者运动诱导的血管适应中的作用已证明 通过DSGP恢复内皮糖萼在T2 D受试者中是可行的，我们现在将研究是否 这种补充将增强运动训练诱导的内皮功能的改善。这将 在因子平衡设计中完成，其中T2 D受试者将随机分配至DSGP或安慰剂组 同时进行和不进行运动训练8周。我们的团队准备将心血管和 糖尿病研究与翻译项目，将发挥持续的，强大的影响，在一个 在概念上、方法论上和治疗上都是新颖的探究层次的数量。的确， 以糖萼为靶点， T2 D退伍军人的适应，从而最大限度地提高运动的心血管益处。