The Skinny on Blood Pressure?

Science Signaling  12 May 2009:
Vol. 2, Issue 70, pp. ec160
DOI: 10.1126/scisignal.270ec160

Although the ability of a high-salt diet (HSD) to promote hypertension in some people has been recognized for decades, the underlying mechanisms remain incompletely understood (see Marvar et al.). Machnik et al. found that rats fed a HSD developed hyperplasia of the lymph capillary network, accompanied by increased numbers of interstitial mononuclear phagocyte system (MPS) cells in skin and changes in skin water and electrolyte content consistent with interstitial Na+ accumulation. Most of the infiltrating MPS cells were immunoreactive for vascular endothelial growth factor-C (VEGF-C, which stimulates lymphangiogenesis), and their depletion inhibited HSD-induced lymph capillary network hyperplasia, as well as HSD-mediated increases in skin abundance of VEGF-C and of the transcription factor TonEBP (tonicity-responsive enhancer binding protein). Moreover, MPS cell depletion exacerbated the HSD-induced increase in mean arterial blood pressure, as well as an HSD-induced increase in skin extracellular volume and decrease in intracellular volume. Similarly, blocking VEGF-C signaling with a soluble VEGF receptor-3 (VEGFR3) construct inhibited HSD-mediated lymphatic hyperplasia and exacerbated the effects of HSD on blood pressure. HSD increased the abundance of endothelial nitric oxide synthase, an effect that was also inhibited by MPS cell depletion and by the soluble VEGFR3 construct. Like VEGF-C, TonEBP colocalized with skin MPS cells; sequence analysis revealed that the Vegfc promoter had two TonEBP binding sequences, and both electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that, in cultured macrophages, high-salt culture medium increased association of TonEBP with the Vegfc promoter. Furthermore, high-salt medium increased the abundance of macrophage VEGF-C and TonEBP mRNA and protein; TonEBP overexpression mimicked the effect of high-salt medium on VEGF-C, whereas TonEBP knockdown blocked it. Intriguingly, plasma from people with refractory hypertension had higher VEGF-C concentrations than did normotensive controls. The authors thus propose that macrophage-dependent secretion of VEGF-C plays a critical role in mediating blood pressure homeostasis in the response to HSD.

A. Machnik, W. Neuhofer, J. Jantsch, A. Dahlmann, T. Tammela, K. Machura, J.-K. Park, F.-X. Beck, D. N. Müller, W. Derer, J. Goss, A. Ziomber, P. Dietsch, H. Wagner, N. van Rooijen, A. Kurtz, K. F. Hilgers, K. Alitalo, K.-U. Eckardt, F. C. Luft, D. Kerjaschki, J. Titze, Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism. Nat. Med. 15, 545–552 (2009). [PubMed]

P. J. Marvar, F. J. Gordon, D. G. Harrison, Blood pressure control: Salt gets under your skin. Nat. Med. 15, 487–488 (2009). [PubMed]