Immune cells control skin lymphatic electrolyte homeostasis and blood pressure
Immune cells control skin lymphatic electrolyte homeostasis and blood pressure
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DOI：
10.1172/jci60113
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发表时间：
2013-07-01
影响因子：
15.9
通讯作者：
Titze, Jens
中科院分区：
文献类型：
--
作者：
Wiig, Helge;Schroeder, Agnes;Titze, Jens
盐敏感性高血压患者皮肤中的钙离子可螯合过多的Na+和Cl-。单核细胞吞噬细胞系统（MPS）细胞被募集到皮肤，感知皮肤中的高渗电解质积聚，并激活张力响应性增强子结合蛋白（TONEBP，也称为NFAT 5）以启动VEGFC的表达和分泌，VEGFC增强经由皮肤淋巴管的电解质清除并增加血管中的eNOS表达。目前尚不清楚这种局部MPS对渗透压的反应是否对全身血压控制重要。在此，我们表明小鼠MPS细胞中TonEBP的缺失阻止了VEGFC对高盐饮食（HSD）的反应并增加了血压。此外，一种阻断淋巴内皮VEGFC受体VEGFR 3的抗体选择性抑制MPS驱动的皮肤毛细淋巴管密度增加，导致皮肤Cl-积聚，并诱导盐敏感性高血压。在表皮角质形成细胞中过表达可溶性VEGFR 3的小鼠表现出皮肤毛细淋巴管发育不良，皮肤中Na+、Cl-和水潴留增加以及盐敏感性高血压。此外，我们发现，HSD升高皮肤渗透压高于血浆水平。这些结果表明，皮肤含有高渗间质液室，其中MPS细胞通过TONEBP和VEGFC/VEGFR 3介导的皮肤毛细淋巴管功能修饰局部组织间质电解质清除来发挥稳态和血压调节控制。
The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice over-expressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.