Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism
Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism
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DOI：
10.1038/nm.1960
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发表时间：
2009-05-01
期刊：
影响因子：
82.9
通讯作者：
Titze, Jens
中科院分区：
文献类型：
--
作者：
Machnik, Agnes;Neuhofer, Wolfgang;Titze, Jens
在盐敏感性高血压中，组织中Na（+）的积累被认为伴随着相应的水潴留，以维持体液的等渗性。我们在这里表明，高盐饮食（HSD）导致大鼠皮肤间质性高渗钠（+）积累，导致淋巴毛细血管网络密度增加和增生。这些影响淋巴系统的机制涉及浸润皮肤间质的单核吞噬细胞系统（MPS）细胞中强直反应增强结合蛋白（TonEBP）的激活。TonEBP结合编码血管内皮生长因子- c （VEGF-C，由Vegfc编码）的基因启动子，引起巨噬细胞分泌VEGF-C。可溶性VEGF受体-3捕获MPS细胞或VEGF- c阻断VEGF- c信号，增加间质高渗容量保留，降低内皮一氧化氮合酶表达并升高血压。我们的数据显示，多磺酸粘多糖细胞中的TonEBP-VEGF-C信号是细胞外体积和血压稳态的主要决定因素，并确定VEGFC是一种渗透敏感、高渗驱动的基因，与盐诱导的高血压密切相关。
In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.