Lymphatic Regulation of Skin Electrolyte Metabolism and Blood Pressure

皮肤电解质代谢和血压的淋巴调节

基本信息

批准号：
9277247
负责人：
Jens Marc Titze
金额：
$ 25.14万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-24 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277247
关键词：
Address Animals Binding Blood Blood Pressure Blood Vessels Body Fluids Buffers Cations Cells Clinical Cutaneous Data Electrolytes Equilibrium Essential Hypertension Etiology Excretory function Extracellular Fluid Extracellular Space Failure Gene Expression Genetic Goals Heart Homeostasis Human Hyperplasia Hypertension Immune Immunological Models Kidney Kidney Failure Laboratories Lymph Lymphatic Lymphatic Capillaries Metabolic Metabolism Modeling Modification Mus Myocardial Infarction NOS3 gene Neuraxis Osmotic Activity Participant Pilot Projects Pre-Clinical Model Promoter Regions Regulation Research Risk Factors Site Skin Sodium Chloride Stream Stress Stroke Systemic blood pressure Testing Tissues Urine VEGFC gene Vascular Endothelial Growth Factor C Water Work blood pressure regulation cardiovascular disorder risk cardiovascular risk factor density dietary salt driving force enhancer binding protein experimental study extracellular in vivo interstitial macrophage metabolic abnormality assessment programs public health relevance receptor receptor binding response salt intake sensor subcutaneous transcription factor

项目摘要

DESCRIPTION (provided by applicant): Primary essential hypertension is the major cardiovascular disease risk factor. Dietary salt intake is a putative driving force of blood pressure elevation; however, the mechanisms of this effect remain unclear. The central nervous system, heart and blood vessels, and kidney are primary participants and the kidney is the putative grand regulator of salt disposition and blood pressure. The overall goal of this work is t address whether or not local regulation of skin electrolyte metabolism is important for blood pressure control. Clinical evidence from pilot studies in humans and preliminary experimental data accumulated in our laboratory, support this hypothesis. Our data point to macrophage-derived vascular endothelial growth factor C (VEGF-C) as a crucial factor controlling skin electrolyte homeostasis. VEGF-C promotes interstitial electrolyte clearance through the cutaneous lymph capillary network. Macrophages induce hyperplasia of subcutaneous lymph capillaries after sensing local Na+ or Cl- overload in the interstitium. The sensing function is accomplished by binding of the transcription factor tonicity-enhancer binding protein (TonEBP) to the promoter region of the VEGF-C gene. The cells exert their regulatory function by increasing VEGF-C expression and secretion. Blockade of this VEGF-C response from macrophages leads to skin electrolyte accumulation and arterial hypertension. We propose a comprehensive program to characterize the importance of TonEBP for macrophage-driven lymphatic regulation of skin electrolyte homeostasis in vivo (Aim 1). We will address whether or not disruption of subcutaneous lymph capillaries by selective VEGF-C depletion in the skin will lead to specific changes in skin electrolyte composition and increase blood pressure systemically (Aim 2). Finally, we will test whether macrophage-derived VEGF-C exerts its blood pressure-lowering effect via receptor binding to blood vessels, or by binding to cutaneous lymph vessels (Aim 3).

描述（由申请人提供）：主要基本高血压是主要的心血管疾病危险因素。饮食盐的摄入量是血压升高的推定驱动力。但是，这种作用的机制尚不清楚。中枢神经系统，心脏和血管以及肾脏是主要参与者，肾脏是盐处置和血压的假定大调节剂。这项工作的总体目标是解决皮肤电解质代谢的局部调节是否对血压控制很重要。来自人类试点研究的临床证据以及我们实验室中积累的初步实验数据支持这一假设。我们的数据指向巨噬细胞衍生的血管内皮生长因子C（VEGF-C）是控制皮肤电解质稳态的关键因素。 VEGF-C通过皮肤淋巴毛细血管网络促进间质电解质清除率。巨噬细胞诱导皮下淋巴毛细血管的增生，在感觉局部Na+或间质中cl-过载后。传感函数是通过结合转录因子增强性增强蛋白（ToneBP）与VEGF-C基因启动子区域的结合来实现的。细胞通过增加VEGF-C表达和分泌来发挥其调节功能。巨噬细胞对这种VEGF-C反应的封锁导致皮肤电解质的积累和动脉高血压。我们提出了一个综合计划，以表征ToneBP对体内皮肤电解质稳态的巨噬细胞驱动淋巴调节的重要性（AIM 1）。我们将解决皮肤中选择性VEGF-C耗竭对皮下淋巴毛细血管的破坏是否会导致皮肤电解质组成的特定变化并系统地增加血压（AIM 2）。最后，我们将测试巨噬细胞来源的VEGF-C是通过与血管结合或与皮肤淋巴管结合的受体结合而降低血压的作用（AIM 3）。