Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency

Patrick Mucka, Nicholas Levonyak, Elena Geretti, Bernadette M.M. Zwaans, Xiaoran Li, Irit Adini, Michael Klagsbrun, Rosalyn M. Adam, Diane R. Bielenberg

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2803-2812
Number of pages10
JournalAmerican Journal of Pathology
Volume186
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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