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).

Public Health Relevance

Elevated blood pressure is a major cause for heart attacks and stroke. We have found that salt and water metabolism in the skin is important for blood pressure regulation. The studies in this proposal will determine in mouse pre-clinical models how immune cells control salt and water balance in the skin and thereby control blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL118579-01
Application #
8483861
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Tolunay, Eser
Project Start
2013-07-24
Project End
2018-05-30
Budget Start
2013-07-24
Budget End
2014-05-30
Support Year
1
Fiscal Year
2013
Total Cost
$371,280
Indirect Cost
$133,280
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Johnson, Randall S; Titze, Jens; Weller, Richard (2016) Cutaneous control of blood pressure. Curr Opin Nephrol Hypertens 25:11-5
Schatz, Valentin; Neubert, Patrick; Schröder, Agnes et al. (2016) Elementary immunology: Na(+) as a regulator of immunity. Pediatr Nephrol :
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Dahlmann, Anke; Dörfelt, Kathrin; Eicher, Florian et al. (2015) Magnetic resonance-determined sodium removal from tissue stores in hemodialysis patients. Kidney Int 87:434-41
Binger, Katrina J; Gebhardt, Matthias; Heinig, Matthias et al. (2015) High salt reduces the activation of IL-4- and IL-13-stimulated macrophages. J Clin Invest 125:4223-38
Hammon, Matthias; Grossmann, Susan; Linz, Peter et al. (2015) 23Na Magnetic Resonance Imaging of the Lower Leg of Acute Heart Failure Patients during Diuretic Treatment. PLoS One 10:e0141336
Speed, Joshua S; Heimlich, J Brett; Hyndman, Kelly A et al. (2015) Endothelin-1 as a master regulator of whole-body Na+ homeostasis. FASEB J 29:4937-44

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