title: 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.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mucka
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Levonyak
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elena
authors.initials: E
authors.lastname: Geretti
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Bernadette M M
authors.initials: BMM
authors.lastname: Zwaans
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Li
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, Massachusetts; Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts. Electronic address: diane.bielenberg@childrens.harvard.edu.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology; D002199:Capillary Permeability; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D042601:Lymphatic Vessels / Q000503:physiopathology; D008209:Lymphedema / Q000235:genetics* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; C491229:Sema3f protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse