Lymphatic Regulation of Skin Electrolyte Metabolism and Blood Pressure

描述（由申请人提供）：原发性高血压是心血管疾病的主要危险因素。膳食盐摄入是血压升高的一个假定驱动力;然而，这种影响的机制仍不清楚。中枢神经系统、心脏和血管以及肾脏是主要的参与者，并且肾脏是盐处置和血压的假定的大调节器。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。来自人类初步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源性血管内皮生长因子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。巨噬细胞在感受到局部Na+或Cl-过载后，诱导皮下淋巴毛细血管增生。通过将转录因子张力增强子结合蛋白（TonEBP）结合到VEGF-C基因的启动子区来实现传感功能。细胞通过增加VEGF-C表达和分泌来发挥其调节功能。阻断巨噬细胞的VEGF-C反应导致皮肤电解质积聚和动脉高血压。我们提出了一个全面的程序来表征TonEBP对巨噬细胞驱动的淋巴调节体内皮肤电解质稳态的重要性（目的1）。我们将讨论通过选择性皮肤VEGF-C耗竭破坏皮下淋巴毛细血管是否会导致皮肤电解质组成的特定变化并全身性升高血压（目的2）。最后，我们将测试巨噬细胞来源的VEGF-C是否通过与血管的受体结合或通过与皮肤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).