Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency.

Abstract

The vasculature influences the progression and resolution of tissue inflammation. Capillaries express vascular endothelial growth factor (VEGF) receptors, including neuropilins (NRPs), which regulate interstitial fluid flow. NRP2, a receptor of VEGFA and semaphorin (SEMA) 3F ligands, is expressed in the vascular and lymphatic endothelia. Previous studies have demonstrated that blocking VEGF receptor 2 attenuates VEGFA-induced vascular permeability. The inhibition of NRP2 was hypothesized to decrease vascular permeability as well. Unexpectedly, massive tissue swelling and edema were observed in Nrp2-/- mice compared with wild-type littermates after delayed-type hypersensitivity reactions. Vascular permeability was twofold greater in inflamed blood vessels in Nrp2-deficient mice compared to those in Nrp2-intact littermates. The addition of exogenous SEMA3F protein inhibited vascular permeability in Balb/cJ mice, suggesting that the loss of endogenous Sema3F activity in the Nrp2-deficient mice was responsible for the enhanced vessel leakage. Functional lymphatic capillaries are necessary for draining excess fluid after inflammation; however, Nrp2-mutant mice lacked superficial lymphatic capillaries, leading to 2.5-fold greater fluid retention and severe lymphedema after inflammation. In conclusion, Nrp2 deficiency increased blood vessel permeability and decreased lymphatic vessel drainage during inflammation, highlighting the importance of the NRP2/SEMA3F pathway in the modulation of tissue swelling and resolution of postinflammatory edema.

• Authors: Patrick Mucka, Nicholas Levonyak, Elena Geretti, Bernadette M M Zwaans, Xiaoran Li, Irit Adini, Michael Klagsbrun, Rosalyn M Adam, Diane R Bielenberg
• Journal: The American journal of pathology (Am J Pathol) Vol. 186 Issue 11 Pg. 2803-2812 (11 2016) ISSN: 1525-2191 [Electronic] United States
• PMID: 27751443 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Nerve Tissue Proteins
• Neuropilin-2
• Sema3f protein, mouse
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Animals
• Blood Vessels (physiopathology)
• Capillary Permeability
• Female
• Humans
• Inflammation (genetics, physiopathology)
• Lymphatic Vessels (physiopathology)
• Lymphedema (genetics, physiopathology)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Nerve Tissue Proteins (genetics, metabolism)
• Neuropilin-2 (deficiency, genetics, metabolism)
• Specific Pathogen-Free Organisms
• Vascular Endothelial Growth Factor A (genetics, metabolism)