Lymphatic Regulation of Skin Electrolyte Metabolism and Blood Pressure

描述（申请人提供）：原发性原发性高血压是主要的心血管疾病危险因素。膳食盐的摄入被认为是血压升高的驱动力；然而，这种影响的机制尚不清楚。中枢神经系统、心脏、血管和肾脏是主要的参与者，肾脏被认为是盐配置和血压的主要调节器。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。来自人体试点研究的临床证据和我们实验室积累的初步实验数据支持这一假设。我们的数据表明巨噬细胞来源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通过皮淋巴毛细血管网促进间质电解质的清除。巨噬细胞在感知间质局部Na+或Cl-超载后诱导皮下淋巴毛细血管增生。这种传感功能是通过转录因子张力增强结合蛋白（TonEBP）结合到VEGF-C基因的启动子区域来实现的。细胞通过增加VEGF-C的表达和分泌来发挥调节功能。巨噬细胞阻断这种VEGF-C反应可导致皮肤电解质积聚和动脉高血压。我们提出了一个综合方案来表征TonEBP在巨噬细胞驱动的淋巴调节体内皮肤电解质稳态中的重要性（目的1）。我们将探讨皮肤中选择性VEGF-C耗竭是否会破坏皮下淋巴毛细血管，从而导致皮肤电解质成分的特定变化和全身血压升高（目的2）。最后，我们将测试巨噬细胞来源的VEGF-C是通过受体与血管结合，还是通过与皮淋巴管结合来发挥其降血压作用（目的3）。

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).