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• W2913182806 abstract "Increased angiogenesis is a characteristic feature of remodeling in asthmatic airways and stems from the imbalance between pro-angiogenic and anti-angiogenic factors. Surprisingly, the factors regulating this process in allergic asthma are poorly defined. Previously, we showed an important role of semaphorins 3E (Sema3E) in growth factor–induced airway smooth muscle proliferation and migration in vitro, and in down-regulating airway inflammation, T helper 2/T helper 17 cytokine response, mucus cell hyperplasia, and airway hyperresponsiveness in vivo. However, the role of Sema3E in airway angiogenesis is not fully understood. Here, we investigated the role of Sema3E in airway angiogenesis using a house dust mite (HDM) murine model of allergic asthma. Intranasal treatment with recombinant Sema3E significantly reduced the expression of angiogenesis markers within the airways of HDM-challenged mice compared with untreated mice. HDM-induced expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 protein were diminished substantially on Sema3E treatment. Interestingly, Sema3E-treated mice showed an enhanced expression of the negative regulator of angiogenesis, soluble VEGF receptor 1, compared with the untreated mice. These events were reversed in Sema3E-deficient mice at baseline or on HDM challenge. Taken together, this study provides the first evidence that Sema3E modulates angiogenesis in allergic asthmatic airways via modulating pro- and anti-angiogenic factors. Increased angiogenesis is a characteristic feature of remodeling in asthmatic airways and stems from the imbalance between pro-angiogenic and anti-angiogenic factors. Surprisingly, the factors regulating this process in allergic asthma are poorly defined. Previously, we showed an important role of semaphorins 3E (Sema3E) in growth factor–induced airway smooth muscle proliferation and migration in vitro, and in down-regulating airway inflammation, T helper 2/T helper 17 cytokine response, mucus cell hyperplasia, and airway hyperresponsiveness in vivo. However, the role of Sema3E in airway angiogenesis is not fully understood. Here, we investigated the role of Sema3E in airway angiogenesis using a house dust mite (HDM) murine model of allergic asthma. Intranasal treatment with recombinant Sema3E significantly reduced the expression of angiogenesis markers within the airways of HDM-challenged mice compared with untreated mice. HDM-induced expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 protein were diminished substantially on Sema3E treatment. Interestingly, Sema3E-treated mice showed an enhanced expression of the negative regulator of angiogenesis, soluble VEGF receptor 1, compared with the untreated mice. These events were reversed in Sema3E-deficient mice at baseline or on HDM challenge. Taken together, this study provides the first evidence that Sema3E modulates angiogenesis in allergic asthmatic airways via modulating pro- and anti-angiogenic factors. Asthma is a heterogeneous atopic disease, characterized by airway hyperresponsiveness, inflammation, and remodeling.1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 2Pascual R.M. Peters S.P. Airway remodeling contributes to the progressive loss of lung function in asthma: an overview.J Allergy Clin Immunol. 2005; 116: 477-486Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 3Shifren A. Witt C. Christie C. Castro M. Mechanisms of remodeling in asthmatic airways.J Allergy. 2012; 2012: 316049Crossref PubMed Google Scholar Airway remodeling refers to the alteration of normal airway structural features including epithelial changes and subepithelial fibrosis, airway smooth muscle (ASM) cell hypertrophy/hyperplasia, goblet cell hyperplasia, and increased angiogenesis.4Halwani R. Al-Muhsen S. Hamid Q. Airway remodeling in asthma.Curr Opin Pharmacol. 2010; 10: 236-245Crossref PubMed Scopus (117) Google Scholar, 5Ribatti D. Puxeddu I. Crivellato E. Nico B. Vacca A. Levi-Schaffer F. Angiogenesis in asthma.Clin Exp Allergy. 2009; 39: 1815-1821Crossref PubMed Scopus (62) Google Scholar Angiogenesis, the sprouting of new blood vessels from pre-existing ones,5Ribatti D. Puxeddu I. Crivellato E. Nico B. Vacca A. Levi-Schaffer F. Angiogenesis in asthma.Clin Exp Allergy. 2009; 39: 1815-1821Crossref PubMed Scopus (62) Google Scholar is a vital process in physiological conditions. However, imbalance between pro- and anti-angiogenic molecules leads to increased angiogenesis in some pathologic conditions. Angiogenesis is one of the hallmarks of airway remodeling and is considered a key determinant of chronic inflammatory disorders including asthma and chronic obstructive pulmonary disease.6Meyer N. Akdis C.A. Vascular endothelial growth factor as a key inducer of angiogenesis in the asthmatic airways.Curr Allergy Asthma Rep. 2013; 13: 1-9Crossref PubMed Scopus (68) Google Scholar It is believed that this pathology arises via activation of several pro-angiogenic growth factors in which vascular endothelial growth factor (VEGF) has been recognized as a master regulator of blood vessel growth in asthmatic airways. In fact, VEGF is a mitogen for endothelial cells and promotes their proliferation and differentiation through the tyrosin kinase receptor VEGF receptor 2 (VEGFR2).7Ribatti D. Crivellato E. “Sprouting angiogenesis”, a reappraisal.Dev Biol. 2012; 372: 157-165Crossref PubMed Scopus (204) Google Scholar VEGF–VEGFR2 signaling in endothelial cells promotes degradation of the extracellular matrix, migration, proliferation, lumen formation, and vessel stabilization.8Kaur S. Leszczynska K. Abraham S. Scarcia M. Hiltbrunner S. Marshall C.J. Mavria G. Bicknell R. Heath V.L. RhoJ/TCL regulates endothelial motility and tube formation and modulates actomyosin contractility and focal adhesion numbers.Arterioscler Thromb Vasc Biol. 2011; 31: 657-664Crossref PubMed Scopus (49) Google Scholar Emerging evidence suggests that a family of axon guidance cues, semaphorins, play a critical role in the development of the nervous system.9Yazdani U. Terman J.R. The semaphorins.Genome Biol. 2006; 7: 211Crossref PubMed Scopus (331) Google Scholar However, recently semaphorins have received extensive attention because of their importance in processes other than neuronal guidance, including cell proliferation, migration, differentiation, and angiogenesis.10Movassagh H. Shan L. Halayko A.J. Roth M. Tamm M. Chakir J. Gounni A.S. Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration.J Allergy Clin Immunol. 2014; 133: 560-567Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 11Sakurai A. Gavard J. Annas-Linhares Y. Basile J.R. Amornphimoltham P. Palmby T.R. Yagi H. Zhang F. Randazzo P.A. Li X. Weigert R. Gutkind J.S. Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras.Mol Cell Biol. 2010; 30: 3086-3098Crossref PubMed Scopus (121) Google Scholar Among eight classes of semaphorins, class 3 is the only secreted form in vertebrates that transduce signals trough their receptor neuropilins and plexins.12Roney K. Holl E. Ting J. Immune plexins and semaphorins: old proteins, new immune functions.Protein Cell. 2013; 4: 17-26Crossref PubMed Scopus (38) Google Scholar Among class 3 semaphorins (Semas), Sema3A has been shown previously to play an essential role in the immunopathogenesis of atopic disorders such as asthma, allergic rhinitis, and atopic dermatitis.13Movassagh H. Tatari N. Shan L. Koussih L. Alsubait D. Khattabi M. Redhu N.S. Roth M. Tamm M. Chakir J. Gounni A.S. Human airway smooth muscle cell proliferation from asthmatics is negatively regulated by semaphorin3A.Oncotarget. 2016; 7: 80238-80251Crossref PubMed Scopus (22) Google Scholar, 14Sawaki H. Nakamura F. Aihara M. Nagashima Y. Komori-Yamaguchi J. Yamashita N. Nakazawa M. Goshima Y. Ikezawa Z. Intranasal administration of semaphorin-3A alleviates sneezing and nasal rubbing in a murine model of allergic rhinitis.J Pharm Sci. 2011; 117: 34-44Crossref PubMed Scopus (27) Google Scholar, 15Shim E.J. Chun E. Kang H.R. Cho S.H. Min K.U. Park H.W. Expression of semaphorin 3A and neuropilin 1 in asthma.J Korean Med Sci. 2013; 28: 1435-1442Crossref PubMed Scopus (15) Google Scholar, 16Yamaguchi J. Nakamura F. Aihara M. Yamashita N. Usui H. Hida T. Takei K. Nagashima Y. Ikezawa Z. Goshima Y. Semaphorin3A alleviates skin lesions and scratching behavior in NC/Nga mice, an atopic dermatitis model.J Invest Dermatol. 2008; 128: 2842-2849Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Furthermore, Sema3E is considered a unique semaphorin because of its ability to signal through the single-pass transmembrane receptor, plexin D1, independently of neuropilins. This characteristic turns it into a repulsive cue; however, the interaction of Sema3E/plexinD1 by Nrp1 or VEGFR2 reverts the function of Sema3E from repulsion to attraction.17Chauvet S. Cohen S. Yoshida Y. Fekrane L. Livet J. Gayet O. Segu L. Buhot M.C. Jessell T.M. Henderson C.E. Mann F. Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development.Neuron. 2007; 56: 807-822Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 18Bellon A. Luchino J. Haigh K. Rougon G. Haigh J. Chauvet S. Mann F. VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain.Neuron. 2010; 66: 205-219Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar Because of the dynamic expression of plexinD1 on endothelial cells at the front of actively sprouting blood vessels, the axis of Sema3E/plexinD1 has emerged as a fundamental pathway in angiogenesis.19Takamatsu H. Kumanogoh A. Diverse roles for semaphorin-plexin signaling in the immune system.Trends Immunol. 2012; 33: 127-135Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 20Oh W.J. Gu C. The role and mechanism-of-action of Sema3E and Plexin-D1 in vascular and neural development.Semin Cell Dev Biol. 2013; 24: 156-162Crossref PubMed Scopus (59) Google Scholar, 21Sakurai A. Doci C.L. Gutkind J.S. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer.Cell Res. 2012; 22: 23-32Crossref PubMed Scopus (108) Google Scholar Sema3E inhibits human ASM cell proliferation and migration, suggesting an important role of this pathway in airway remodeling.10Movassagh H. Shan L. Halayko A.J. Roth M. Tamm M. Chakir J. Gounni A.S. Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration.J Allergy Clin Immunol. 2014; 133: 560-567Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Sema3E is also critical in neutrophil migration in vitro and in vivo.22Movassagh H. Saati A. Nandagopal S. Mohammed A. Tatari N. Shan L. Duke-Cohan J.S. Fowke K.R. Lin F. Gounni A.S. Chemorepellent semaphorin 3E negatively regulates neutrophil migration in vitro and in vivo.J Immunol. 2017; 198: 1023-1033Crossref PubMed Scopus (30) Google Scholar Furthermore, Sema3e-deficient mice showed an enhanced airway hyper-responsiveness, airway inflammation, and mucus cell hyperplasia,23Movassagh H. Shan L. Mohammed A. Halayko A.J. Gounni A.S. Semaphorin 3E deficiency exacerbates airway inflammation, hyperresponsiveness, and remodeling in a mouse model of allergic asthma.J Immunol. 2017; 198: 1805-1814Crossref PubMed Scopus (27) Google Scholar suggesting a key role of this axis in allergic asthma. However, the role of Sema3E in airway angiogenesis is not known. Here, we investigated the role of Sema3E in allergen-induced angiogenesis using a mouse model of allergic asthma. Six- to 8-week-old immunocompetent female Bagg albino/c mice, Sema3e−/− mice (129P2 Bl/6; kindly provided by Dr. Fanny Mann, Developmental Biology Institute of Marseille Luminy, Université de la Méditerranée, Marseille, France), and their littermate wild-type control were used in this study.24Choi Y.I. Duke-Cohan J.S. Ahmed W.B. Handley M.A. Mann F. Epstein J.A. Clayton L.K. Reinherz E.L. PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.Immunity. 2008; 29: 888-898Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar All animals were maintained at the Centre of Animal Care Services of the University of Manitoba under specific pathogen-free conditions and used in accordance with the Canadian Council for Animal Care guidelines. Induction of allergic asthma was performed as described in Figure 1A. In brief, mice were sensitized and challenged intranasally with HDM resuspended in sterile saline (25 μg) (Dermatophagoides pteronyssinus; Greer Laboratories Inc., Lenoir, NC) for 5 consecutive days for 2 weeks. Murine Sema3E–fragment crystallizable region (Fc region) recombinant protein was produced as fusion protein N-terminal to a functional mouse γ2c Fc domain using Chinese hamster ovary cells. Secreted Sema3E-Fc protein was purified by protein A-affinity chromatography as previously described.24Choi Y.I. Duke-Cohan J.S. Ahmed W.B. Handley M.A. Mann F. Epstein J.A. Clayton L.K. Reinherz E.L. PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.Immunity. 2008; 29: 888-898Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Sema3E-Fc (10 μg/kg) or Fc-Ig control was administered intranasally 1 hour before each HDM exposure (25 μg). Saline-treated mice were used as a control group. In different experiments, HDM was intranasally administered to either Sema3e−/− mice or wild-type littermates according to Figure 1A. Control mice received saline instead of HDM. Lung mechanics were measured using the FlexiVent ventilator (SCIREQ, Montreal, Quebec, Canada) as previously described.25Ryu M.H. Jha A. Ojo O.O. Mahood T.H. Basu S. Detillieux K.A. Nikoobakht N. Wong C.S. Loewen M. Becker A.B. Halayko A.J. Chronic exposure to perfluorinated compounds: impact on airway hyperresponsiveness and inflammation.Am J Physiol Lung Cell Mol Physiol. 2014; 307: L765-L774Crossref PubMed Scopus (42) Google Scholar In brief, HDM or saline-sensitized and challenged mice underwent a tracheotomy. Then, an increasing gradient of methacholine dose (0, 3, 6, 12, 25, and 50 mg/mL) was administered intratracheally with a 5-minute interval between the doses and lung function parameters were performed including airway resistance, tissue resistance, and tissue elastance. The total number of leukocytes in bronchoalveolar lavage fluid and differential cell counts was performed as described previously.26Asosingh K. Cheng G. Xu W. Savasky B.M. Aronica M.A. Li X. Erzurum S.C. Nascent endothelium initiates Th2 polarization of asthma.J Immunol. 2013; 190: 3458-3465Crossref PubMed Scopus (25) Google Scholar Formalin-fixed tissues were paraffin-embedded, and 5-μm–thick sections were cut and stained with hematoxylin and eosin for evaluating the level of cell infiltration.27Duan W. Chan J.H. Wong C.H. Leung B.P. Wong W.S. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model.J Immunol. 2004; 172: 7053-7059Crossref PubMed Scopus (249) Google Scholar Tissue sections were stained as previously described.10Movassagh H. Shan L. Halayko A.J. Roth M. Tamm M. Chakir J. Gounni A.S. Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration.J Allergy Clin Immunol. 2014; 133: 560-567Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Briefly, deparaffinized 5-μm tissue sections were washed and incubated with blocking solution (1% bovine serum albumin, 0.1% cold fish skin gelatin, and 5% second animal serum in Tris-buffered saline) for 45 minutes at room temperature. Sections were incubated for 3 hours at room temperature with rabbit anti-mouse von Willebrand factor (vWF) polyclonal antibody (1:400; Dako, Santa Clara, CA), rabbit anti-mouse CD31 polyclonal (1:50; Abcam, Toronto, ON, Canada), goat anti-mouse VEGF polyclonal antibody (1:20; R&D Systems, Minneapolis, MN), goat anti-mouse VEGFR1 polyclonal antibody (1:20; R&D Systems), rabbit anti-mouse VEGFR2 polyclonal antibody (1:200; Biorbyt, San Francisco, CA), mouse anti-human neutrophil elastase monoclonal antibody (1:20; Dako), and rabbit anti-mouse major basic protein polyclonal antibody (1:40, Cloud-Clone Corp., Katy, TX). Tissue sections were incubated with Alexa Flour–568 goat anti-rabbit IgG, Alexa Flour–488 chicken anti-goat IgG, or Alexa Flour–488 goat anti-mouse IgG (heavy and light) (Life Technologies, Burlington, ON, Canada) for 1 hour at room temperature. Slides then were washed extensively for 3 × 5 minutes with Tris-buffered saline and counterstained with ProLong Gold Antifade mountant with DAPI (Life Technologies). Images were acquired using a digital Zeiss Axioskop 2 mot plus microscope using AxioVision Rel software version 4.8 (Carl Zeiss Microscopy, LLC, Thornwood, NY). Immunofluorescence staining of vWF and CD31 was analyzed quantitatively by counting the number of blood vessels positively stained for vWF and CD31 in five randomly chosen high-power fields of four tissue sections from each mouse.28Lee L.T. Chen P.H. Chang C.T. Wang J. Wong Y.K. Wang H.W. Quantitative physiology and immunohistochemistry of oral lesions.Biomed Opt Express. 2013; 4: 2696-2709Crossref PubMed Scopus (5) Google Scholar The result was reported as an average of the number of red blood vessels in each group.28Lee L.T. Chen P.H. Chang C.T. Wang J. Wong Y.K. Wang H.W. Quantitative physiology and immunohistochemistry of oral lesions.Biomed Opt Express. 2013; 4: 2696-2709Crossref PubMed Scopus (5) Google Scholar Moreover, the result of VEGF, VEGFR1, and VEGFR2 staining was analyzed quantitatively by calculating the signal mean intensity of 20 randomly chosen high-power fields from each group using ImageJ software version 1.48v (NIH, Bethesda, MD; https://imagej.nih.gov/ij). The result was reported as the mean intensity for each group. Lung samples were homogenized in cold homogenization buffer containing RPMI (Gibco, Life Technologies, Burlington, ON, Canada), Protease Inhibitor Cocktail (Sigma-Aldrich, Life Science, Oakville, ON, Canada), and phenylmethylsulfonyl fluoride (Sigma-Aldrich, Life Science). After centrifugation of the homogenates at 10,000 × g for 15 minutes, supernatants were collected. The protein concentration of each sample was determined using the bicinchoninic acid protein assay kit, according to the manufacturer's instructions (EMD Millipore). The concentration of VEGF-A and soluble VEGFR1 (sVEGFR1) were quantitated using mouse VEGF and mouse sVEGFR1 DuoSet Enzyme-Linked Immunosorbent Assay (ELISA) kits (R&D Systems). The sensitivity limits of VEGF-A and the sVEGFR1 assay were 15.6 pg/mL and 150 pg/mL, respectively. Total RNA was extracted from the whole lung by using TRIzol (Invitrogen, Life Technologies, Burlington, ON, Canada) according to the manufacturer's protocol. RNA (2 μg) was subjected to MultiScribe Reverse Transcriptase to synthesize cDNA (Applied Biosystems, Foster City, CA) in a total volume of 20 μL. cDNA of each sample and sequence-specific Vegfr1 primer (forward: 5′-TCACAGATGTGCCGAATG-3′, reverse: 5′-CGTAGCAGAATCCAGGTAATG-3′) and Gapdh primer (forward: 5′-AACTTTGGCATTGTGGAAGG-3′, reverse: 5′-ACACATTGGGGGTAGGAACA-3′) (10 μmol/L) were added to SYBR Select Master Mix (Applied Biosystems). The amplification of target genes was calculated by normalizing to the amplification of Gapdh and then normalizing to control groups. Then the normalized values were expressed as fold increase/decrease of relative quantitative over the values calculated with other groups. Results are expressed as the means ± SEM. Differences between the groups were analyzed by one-way analysis of variance first to determine if any significant differences may exist among various experimental groups, and then Bonferroni post-tests were performed to detect statistically significant differences in each pair of experimental groups using GraphPad Prism 5.04 (Graphpad Software Inc., San Diego, CA). P values <0.05 were considered statistically significant. Sema3E recombinant protein reduces HDM-induced airway hyper-responsiveness and airway inflammation.29Movassagh H. Shan L. Duke-Cohan J.S. Halayko A.J. Uzonna J.E. Gounni A.S. Semaphorin 3E alleviates hallmarks of house dust mite-induced allergic airway disease.Am J Pathol. 2017; 187: 1566-1576Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In brief, Bagg albino/c mice were pretreated with Sema3E-Fc or Fc fragment Ig control (Fc Ig, 10 μg/kg) 1 hour before intranasal instillation of HDM as described in Figure 1A, and response to methacholine challenge was recorded. The level of different features of airway hyper-responsiveness including airway and tissue resistance and tissue elastance were increased in the HDM-challenged, Fc-pretreated mice and was attenuated significantly in the Sema3E-pretreated group (Supplemental Figure S1). Similarly, the level of inflammation in bronchoalveolar lavage fluid was examined by performing a cytologic examination on cytospin preparations by differential quick staining. The total bronchoalveolar lavage fluid cell count was reduced significantly in Sema3E-Fc–treated mice compared with HDM-challenged and Fc-treated controls (Figure 1B). In particular, Sema3E-Fc treatment reduced the level of granulocytes, mainly eosinophils (Figure 1C), and, to a lesser extent, neutrophils (Figure 1D). It did not significantly change the level of macrophages/mononuclear cells and lymphocytes in the airways (Figure 1, E and F). Photomicrographs of stained sections show an increased level of peribronchial inflammation in HDM-challenged mice. However, the infiltration of inflammatory cells was reduced in the Sema3E-treated group (Figure 1G), which was confirmed further by decreased immunoreactivity of neutrophil elastase and major basic protein (Figure 1H). Taken together, these data suggest that Sema3E reduces the levels of HDM-induced airway inflammation, particularly eosinophils. Previous studies have shown that the number of blood vessels is increased significantly in the airways of asthmatic patients in comparison with healthy controls.30Hoshino M. Aoike N. Takahashi M. Nakamura Y. Nakagawa T. Increased immunoreactivity of stromal cell-derived factor-1 and angiogenesis in asthma.Eur Respir J. 2003; 21: 804-809Crossref PubMed Scopus (55) Google Scholar, 31Hoshino M. Nakamura Y. Hamid Q.A. Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma.J Allergy Clin Immunol. 2001; 107: 1034-1038Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 32Hoshino M. Takahashi M. Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis.J Allergy Clin Immunol. 2001; 107: 295-301Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar To examine the effect of Sema3E on HDM-induced angiogenesis in mice, immunofluorescence staining was performed using anti-vWF antibody. vWF is considered the most specific marker for lung endothelial cells.33Middleton J. Americh L. Gayon R. Julien D. Mansat M. Mansat P. Anract P. Cantagrel A. Cattan P. Reimund J.M. Aguilar L. Amalric F. Girard J.P. A comparative study of endothelial cell markers expressed in chronically inflamed human tissues: MECA-79, Duffy antigen receptor for chemokines, von Willebrand factor, CD31, CD34, CD105 and CD146.J Pathol. 2005; 206: 260-268Crossref PubMed Scopus (103) Google Scholar CD31, a marker characterizing endothelial cells, also was used to stain blood vessels.34Pusztaszeri M.P. Seelentag W. Bosman F.T. Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues.J Histochem Cytochem. 2006; 54: 385-395Crossref PubMed Scopus (585) Google Scholar The number of newly formed blood vessels, as shown by vWF and CD31 staining, was reduced significantly in bronchial sections of the Sema3E-Fc treatment group compared with the Fc-Ig–treated HDM-challenged mice (Figure 2A and Supplemental Figure S2). To ascertain the importance of Sema3E in airway neoangiogenesis, Sema3e-/- and littermate control mice were subjected to HDM challenge (Figure 1A). A significant increase in immunoreactivity of vWF in Sema3e-/- mice was detected at baseline and after HDM challenge compared with the wild-type littermates (Figure 2B). These data suggest that Sema3E reduces new blood vessel formation in the lung in a mouse model of HDM-induced airway inflammation. Previous studies have shown a key role of VEGF in the proliferation and differentiation of endothelial cells via binding to the high-affinity tyrosine kinase receptor, VEGFR2, which culminates in an increased level of angiogenesis.7Ribatti D. Crivellato E. “Sprouting angiogenesis”, a reappraisal.Dev Biol. 2012; 372: 157-165Crossref PubMed Scopus (204) Google Scholar, 35Ferrara N. Gerber H.P. LeCouter J. The biology of VEGF and its receptors.Nat Med. 2003; 9: 669-676Crossref PubMed Scopus (7822) Google Scholar, 36Dimmeler S. Zeiher A.M. Endothelial cell apoptosis in angiogenesis and vessel regression.Circ Res. 2000; 87: 434-439Crossref PubMed Scopus (359) Google Scholar, 37Moriya J. Minamino T. Tateno K. Okada S. Uemura A. Shimizu I. Yokoyama M. Nojima A. Okada M. Koga H. Komuro I. Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis.Exp Cell Res. 2010; 106: 391-398Google Scholar, 38Ferrari G. Pintucci G. Seghezzi G. Hyman K. Galloway A.C. Mignatti P. VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis.Proc Natl Acad Sci U S A. 2006; 103: 17260-17265Crossref PubMed Scopus (134) Google Scholar To investigate whether the effect of Sema3E on reducing blood vessels in the HDM mouse model of allergic asthma is mediated via VEGF, ELISA and immunofluorescence staining were performed to probe for VEGF level in lung homogenate and lung sections, respectively. The level of VEGF secretion was reduced significantly in lung homogenate of HDM-challenged and Sema3E-treated mice compared with HDM-challenged alone (Figure 3A). Furthermore, immunofluorescence staining showed a reduced level of VEGF in lung sections of HDM-challenged and Sema3E-treated mice compared with HDM-challenged alone. VEGF staining was predominantly positive in epithelial cell layers, and to a lesser extent in myofibroblasts and inflammatory cells (Figure 3B). Conversely, a significant increase in pulmonary VEGF immunoreactivity was observed in Sema3e-/- mice compared with the WT littermates (Figure 3C), which was confirmed further by ELISA both at baseline and on HDM exposure (Figure 3D). VEGFR2 is recognized as a major mediator of angiogenic and mitogenic effects of VEGF.35Ferrara N. Gerber H.P. LeCouter J. The biology of VEGF and its receptors.Nat Med. 2003; 9: 669-676Crossref PubMed Scopus (7822) Google Scholar, 39Zhang N. Fang Z. Contag P.R. Purchio A.F. West D.B. Tracking angiogenesis induced by skin wounding and contact hypersensitivity using a Vegfr2-luciferase transgenic mouse.Blood. 2004; 103: 617-626Crossref PubMed Scopus (104) Google Scholar The effect of in vivo Sema3E treatment on VEGFR2 expression was studied on blood vessels by performing immunofluorescence staining on lung sections. The expression of VEGFR2 staining was down-regulated significantly in lung vessels of HDM-challenged and Sema3E-treated mice in comparison with HDM-challenged alone (Figure 4A). Genetic deletion of Sema3e was associated with basal and HDM increased expression of VEGFR2 (Figure 4B). Overall, Sema3E plays an important role in negative regulation of angiogenesis in the HDM model of asthma by controlling VEGF and VEGFR2 expression within the airways. sVEGFR1, also known as soluble Flt-1, is produced upon alternative splicing of the VEGFR1 gene. sVEGFR1 acts as a decoy receptor by inhibiting the binding of VEGF to VEGFR2 and negatively regulates the activity of VEGF on the vascular endothelium.35Ferrara N. Gerber H.P. LeCouter J. The biology of VEGF and its receptors.Nat Med. 2003; 9: 669-676Crossref PubMed Scopus (7822) Google Scholar, 40Bernatchez P.N. Soker S. Sirois M.G. Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent.Genome Biol. 1999; 274: 31047-31054Scopus (239) Google Scholar, 41Cai J. Jiang W.G. Ahmed A. Boulton M. Vascular endothelial growth factor-induced endothelial cell proliferation is regulated by interaction between VEGFR-2, SH-PTP1 and eNOS.J Korean Med Sci. 2006; 71: 20-31Google Scholar, 42Kendall R.L. Thomas K.A. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci U S A. 1993; 90: 10705-10709Crossref PubMed Scopus (1189) Google Scholar, 43Zanini A. Chetta A. Imperatori A.S. Spanevello A. Olivieri D. The role of the bronchial microvasculature in the airway remodelling in asthma and COPD.Respir Res. 2010; 11: 132Crossref PubMed Scopus (88) Google Scholar To investigate whether the effect of Sema3E on reducing new blood vessels in our mouse model is related to sVEGFR1 production; ELISA, quantitative PCR, and immunofluorescence staining were performed. The level of sVEGFR1 was increased significantly in lung homogenate of HDM-challenged and Sema3E-Fc–treated mice in comparison with HDM-challenged alone as detected by ELISA (Figure 5A). In addition, gene expression study and immunofluorescence staining confirmed our results on the role of Sema3E in inducing sVEGFR1 produ" @default.
• W2913182806 created "2019-02-21" @default.
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• W2913182806 date "2019-04-01" @default.
• W2913182806 modified "2023-10-09" @default.
• W2913182806 title "Semaphorin 3E Inhibits House Dust Mite–Induced Angiogenesis in a Mouse Model of Allergic Asthma" @default.
• W2913182806 cites W1562971597 @default.
• W2913182806 cites W1567249948 @default.
• W2913182806 cites W1953191479 @default.
• W2913182806 cites W1965295093 @default.
• W2913182806 cites W1966689324 @default.
• W2913182806 cites W1976911328 @default.
• W2913182806 cites W1978268544 @default.
• W2913182806 cites W1986469266 @default.
• W2913182806 cites W1986778052 @default.
• W2913182806 cites W1992507453 @default.
• W2913182806 cites W2000292756 @default.
• W2913182806 cites W2002392082 @default.
• W2913182806 cites W2003686790 @default.
• W2913182806 cites W2008324333 @default.
• W2913182806 cites W2025136793 @default.
• W2913182806 cites W2044217758 @default.
• W2913182806 cites W2047607520 @default.
• W2913182806 cites W2053221827 @default.
• W2913182806 cites W2063313926 @default.
• W2913182806 cites W2069267570 @default.
• W2913182806 cites W2073676627 @default.
• W2913182806 cites W2074326572 @default.
• W2913182806 cites W2076086302 @default.
• W2913182806 cites W2079670549 @default.
• W2913182806 cites W2081351965 @default.
• W2913182806 cites W2086283601 @default.
• W2913182806 cites W2089758247 @default.
• W2913182806 cites W2090393106 @default.
• W2913182806 cites W2091014900 @default.
• W2913182806 cites W2091456307 @default.
• W2913182806 cites W2092068315 @default.
• W2913182806 cites W2092902440 @default.
• W2913182806 cites W2103457206 @default.
• W2913182806 cites W2104263302 @default.
• W2913182806 cites W2108877784 @default.
• W2913182806 cites W2112251383 @default.
• W2913182806 cites W2120335426 @default.
• W2913182806 cites W2123388791 @default.
• W2913182806 cites W2127203245 @default.
• W2913182806 cites W2128633611 @default.
• W2913182806 cites W2129297330 @default.
• W2913182806 cites W2129600117 @default.
• W2913182806 cites W2129752592 @default.
• W2913182806 cites W2130853706 @default.
• W2913182806 cites W2133715809 @default.
• W2913182806 cites W2135555439 @default.
• W2913182806 cites W2138984761 @default.
• W2913182806 cites W2143340268 @default.
• W2913182806 cites W2155611085 @default.
• W2913182806 cites W2160926771 @default.
• W2913182806 cites W2531867756 @default.
• W2913182806 cites W2533218268 @default.
• W2913182806 cites W2560826436 @default.
• W2913182806 cites W2582652923 @default.
• W2913182806 cites W2613045305 @default.
• W2913182806 cites W2624707987 @default.
• W2913182806 cites W4253566969 @default.
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