Abstract 630: Lymphocytes Exert Homeostatic Immune Function For Blood Pressure Control Via Inhibition Of The MPS / VEGF-C Regulatory Axis.
Background: We have shown previously that electrolyte homeostasis is characterized by local regulation of water-free Na+ storage in the skin. Macrophages infiltrate the Na+ overloaded skin interstitium and induce interstitial electrolyte clearance by TonEBP- / VEGF-C-driven lymph capillary network hyperplasia, therefore providing a buffering mechanism for hypertension. Whether such extrarenal control for volume and blood pressure homeostasis is exclusively achieved by innate immune cells, or whether components of the adaptive immune system modulate this macrophage-specific response, is unclear. We hypothesized that lymphocytes might influence macrophage/TonEBP/VEGF-C driven regulation of skin electrolyte homeostasis and thereby modulate blood pressure.
Methods: Seven wt and six RAG-/--mice, which have no B- or T-cells, were fed a low-salt diet for 2 consecutive weeks. In the end of the experiments, blood pressure was measured via an arterial line, skin electrolyte composition was analyzed, and the macrophage/TonEBP/VEGF-C regulatory axis was characterized.
Results: RAG-/--mice had lower skin Na+ (0.11±0.01 vrs. 0.15±0.04 mmol/g; P<0.05) and water content (1.06±0.14 vrs. 1.42±0.35 ml/g; P<0.05) than wt mice, showed increased VEGF-C mRNA expression in the skin (1.78±0.41 vrs. 1.00±0.66 arbitrary units; P<0.05), and displayed hyperplastic subcutaneous lymph capillaries (7.0±1.8 vrs. 4.0±2.0 arbitrary units; P<0.05). In parallel with this extracellular volume loss, mean arterial blood pressure was reduced in RAG-/- mice (97±8 vrs. 108±7 mmHg; P<0.05).
Conclusion: We conclude that the absence of B- and T-cells disinhibits VEGF-C expression from subcutaneous macrophages, resulting in inadequate hyperplasia of subcutaneous vessels and extracellular volume loss from skin, which leads to hypotension in RAG-/--mice. The findings suggest that B- or T-cells are part of a regulatory network in which macrophages modulate interstitial electrolyte homeostasis and blood pressure.
Perspectives: Additional experiments in mice with selective B- or T-cell depletion, and adoptive transfer of B- or T-lymphocyte subsets into RAG-/--mice will allow identification of specific lymphocyte subpopulations involved in inhibition of the TonEBP/VEGF-C regulatory axis in macrophages. Further experiments will also focus on molecular mechanisms of lymphocyte / macrophage interaction. We aim to demonstrate that cells of the innate and adaptive immune system form a network of "homeostatic immune function" for the control of electrolyte and blood pressure homeostasis.
- © 2012 by American Heart Association, Inc.