00823nas a2200253 4500008004100000022001400041245012000055210007100175260001600246300001000262490000700272100002100279700001900300700001800319700001800337700002800355700001700383700002100400700002100421700002200442700002100464700002200485856006200507 2020 eng d a2324-926900aInvestigation on the role of biallelic variants in VEGF‐C found in a patient affected by Milroy‐like lymphedema0 aInvestigation on the role of biallelic variants in VEGF‐C found cFeb-06-2022 ae13890 v001 aMukenge, Sylvain1 aJha, Sawan, K.1 aCatena, Marco1 aManara, Elena1 aLeppänen, Veli‐Matti1 aLenti, Elisa1 aNegrini, Daniela1 aBertelli, Matteo1 aBrendolan, Andrea1 aJeltsch, Michael1 aAldrighetti, Luca uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/mgg3.138900911nas a2200217 4500008004100000245006800041210006700109260001600176300003100192520016400223100001900387700001500406700001700421700002600438700002100464700002300485700002100508700001900529700001800548856012700566 2020 eng d00aVEGF-C Protects the Integrity of Bone Marrow Perivascular Niche0 aVEGFC Protects the Integrity of Bone Marrow Perivascular Niche c2020/07/31/ aaccepted - for publication3 aKey Points. Vegfc deletion in endothelial or LepR+ cells compromises the bone marrow perivascular niche and hematopoietic stem cell maintenance.Exogenous admin1 aFang, Shentong1 aChen, Shuo1 aNurmi, Harri1 aLeppänen, Veli-Matti1 aJeltsch, Michael1 aScadden, David, T.1 aSilberstein, Lev1 aMikkola, Hanna1 aAlitalo, Kari uhttps://ashpublications.org/blood/article/doi/10.1182/blood.2020005699/463465/VEGF-C-Protects-the-Integrity-of-Bone-Marrow02348nas a2200277 4500008004100000245010600041210006900147260001200216300001400228490000700242520151100249100001901760700001901779700002201798700001601820700002401836700001701860700001401877700001701891700001601908700002101924700001601945700002101961700002201982856006602004 2015 eng d00aIschemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts0 aIschemiaReperfusion Injury Enhances Lymphatic Endothelial VEGFR3 c12/2015 a1160-11720 v163 aOrgan damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia–reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection.1 aDashkevich, A.1 aRaissadati, A.1 aSyrjälä, S., O.1 aZarkada, G.1 aKeränen, M., A. I.1 aTuuminen, R.1 aKrebs, R.1 aAnisimov, A.1 aJeltsch, M.1 aLeppänen, V.-M.1 aAlitalo, K.1 aNykänen, A., I.1 aLemström, K., B. uhttp://onlinelibrary.wiley.com/doi/10.1111/ajt.13564/abstract02689nas a2200469 4500008004100000022001400041245014300055210006900198260001300267300001300280490000800293520127600301653001201577653001201589653003401601653002801635653001801663653001801681653002001699653002501719653001101744653002101755653000901776653001901785653003601804653002801840653002101868653002401889653004101913653001401954653002301968100002701991700002102018700001902039700002102058700002102079700001902100700002102119700001802140700002202158856003902180 2013 eng d a1477-912900aA truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development.0 atruncation allele in vascular endothelial growth factor c reveal c2013 Apr a1497-5060 v1403 a
Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor Flt4. When expressed in endothelial cells, vegfc(um18) could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis.
10aAlleles10aAnimals10aAnimals, Genetically Modified10aAutocrine Communication10aBlood Vessels10aCell Movement10aCodon, Nonsense10aEmbryo, Nonmammalian10aFemale10aLymphatic System10aMice10aMice, Knockout10aNeovascularization, Physiologic10aParacrine Communication10aProtein Isoforms10aSignal Transduction10aVascular Endothelial Growth Factor C10aZebrafish10aZebrafish Proteins1 aVillefranc, Jacques, A1 aNicoli, Stefania1 aBentley, Katie1 aJeltsch, Michael1 aZarkada, Georgia1 aMoore, John, C1 aGerhardt, Holger1 aAlitalo, Kari1 aLawson, Nathan, D uhttps://jeltsch.org/Villefranc201303199nas a2200529 4500008004100000022001400041245013000055210006900185260001300254300001200267490000800279520162800287653002201915653001201937653002901949653001501978653001701993653002002010653003702030653002002067653002102087653001502108653002002123653002102143653002002164653001702184653002202201653001602223653001602239653000902255653002402264653001502288653001202303653003202315653001802347653004102365653005002406100001802456700002302474700002302497700002102520700002202541700002602563700002302589700002302612856003402635 2012 eng d a1525-219100aCritical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.0 aCritical role of VEGFCVEGFR3 signaling in innate and adaptive im c2012 Nov a1607-200 v1813 aChronic inflammation, a hallmark of obliterative bronchiolitis, is known to induce lymphangiogenesis. We therefore studied the role of lymphangiogenic vascular endothelial growth factor C (VEGF-C), its receptor VEGFR-3, and lymphangiogenesis during development of experimental obliterative bronchiolitis [ie, obliterative airway disease (OAD)] in rat tracheal allografts. The functional importance of VEGF-C was investigated by adenovirus-mediated overexpression of VEGF-C (AdVEGF-C), and by inhibition of VEGF-C activity with VEGFR-3-Ig (AdVEGFR-3-Ig). Analyses included histology, immunohistochemistry, and real-time RT-PCR 10 and 30 days after transplantation. In the course of OAD development, lymphangiogenesis was induced in the airway wall during the alloimmune response, which was reversed by cyclosporine A in a dose-dependent fashion. VEGF-C overexpression in tracheal allografts induced epithelial activation, neutrophil chemotaxis, and a shift toward a Th17 adaptive immune response, followed by enhanced lymphangiogenesis and the development of OAD. In contrast, inhibition of VEGF-C activity with VEGFR-3-Ig inhibited lymphangiogenesis and angiogenesis and reduced infiltration of CD4(+) T cells and the development of OAD. Lymphangiogenesis was linked to T-cell responses during the development of OAD, and VEGF-C/VEGFR-3 signaling modulated innate and adaptive immune responses in the development of OAD in rat tracheal allografts. Our results thus suggest VEGFR-3-signaling as a novel strategy to regulate T-cell responses in the development of obliterative bronchiolitis after lung transplantation.
10aAdaptive Immunity10aAnimals10aBronchiolitis Obliterans10aChemotaxis10aCyclosporine10aDendritic Cells10aDose-Response Relationship, Drug10aDown-Regulation10aEpithelial Cells10aEpithelium10aGraft Rejection10aImmunity, Innate10aImmunoglobulins10aInflammation10aLymphangiogenesis10aMacrophages10aNeutrophils10aRats10aSignal Transduction10aTh17 Cells10aTrachea10aTransplantation, Homologous10aUp-Regulation10aVascular Endothelial Growth Factor C10aVascular Endothelial Growth Factor Receptor-31 aKrebs, Rainer1 aTikkanen, Jussi, M1 aRopponen, Jussi, O1 aJeltsch, Michael1 aJokinen, Janne, J1 aYlä-Herttuala, Seppo1 aNykänen, Antti, I1 aLemström, Karl, B uhttps://jeltsch.org/Krebs201200655nas a2200217 4500008004100000245010700041210006900148260001100217300001600228490000700244100001300251700001700264700001700281700001500298700001600313700002200329700001700351700001700368700001800385856003400403 2011 eng d00aVEGF-C/VEGFR-3 Signaling Regulates Inflammatory Response in Development of Obliterative Airway Disease0 aVEGFCVEGFR3 Signaling Regulates Inflammatory Response in Develop c2011// aS118 - S1180 v301 aKrebs, R1 aTikkanen, JM1 aRopponen, JO1 aJeltsch, M1 aJokinen, JJ1 aYlä-Herttuala, S1 aKoskinen, PK1 aNykänen, AI1 aLemström, KB uhttps://jeltsch.org/Krebs201101603nas a2200265 4500008004100000245011900041210006900160260001400229300001300243490000700256520077800263100002101041700002001062700002001082700002101102700002201123700002101145700002301166700002301189700001601212700002101228700002101249700001801270856004901288 2010 eng d00aClaudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development0 aClaudinlike protein 24 interacts with the VEGFR2 and VEGFR3 path c2010/May/ a875 - 800 v243 aThe Claudin-like protein of 24 kDa (CLP24) is a hypoxia-regulated transmembrane protein of unknown function. We show here that clp24 knockdown in Danio rerio and Xenopus laevis results in defective lymphatic development. Targeted disruption of Clp24 in mice led to enlarged lymphatic vessels having an abnormal smooth muscle cell coating. We also show that the Clp24(-/-) phenotype was further aggravated in the Vegfr2(+/LacZ) or Vegfr3(+/LacZ) backgrounds and that CLP24 interacts with vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGFR-3 and attenuates the transcription factor CREB phosphorylation via these receptors. Our results indicate that CLP24 is a novel regulator of VEGFR-2 and VEGFR-3 signaling pathways and of normal lymphatic vessel structure.1 aSaharinen, Pipsa1 aHelotera, Hanna1 aMiettinen, Juho1 aNorrmen, Camilla1 aD'Amico, Gabriela1 aJeltsch, Michael1 aLangenberg, Tobias1 aVandevelde, Wouter1 aNy, Annelii1 aDewerchin, Mieke1 aCarmeliet, Peter1 aAlitalo, Kari uhttp://view.ncbi.nlm.nih.gov/pubmed/2043942802098nas a2200385 4500008004100000245011800041210006900159260001400228300001400242490000700256520095200263100001301215700001501228700001901243700001901262700001601281700002001297700002101317700002001338700002401358700002901382700002001411700002901431700001601460700002501476700002501501700002301526700002101549700001901570700001801589700001801607700002101625700001701646856004901663 2008 eng d00aReevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium0 aReevaluation of the role of VEGFB suggests a restricted role in c2008/Sep/ a1614 - 200 v283 aOBJECTIVE: The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. METHODS AND RESULTS: We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B(-/-)) or overexpressing VEGF-B(167). After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B(167) overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B(167) overexpression failed to enhance vascular growth in the skin or ischemic limb. CONCLUSIONS: VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.1 aLi, Xuri1 aTjwa, Marc1 aVan Hove, Inge1 aEnholm, Berndt1 aNeven, Elke1 aPaavonen, Karri1 aJeltsch, Michael1 aJuan, Toni Diez1 aSievers, Richard, E1 aChorianopoulos, Emmanuel1 aWada, Hiromichi1 aVanwildemeersch, Maarten1 aNoel, Agnes1 aFoidart, Jean-Michel1 aSpringer, Matthew, L1 aDegenfeld, Georges1 aDewerchin, Mieke1 aBlau, Helen, M1 aAlitalo, Kari1 aEriksson, Ulf1 aCarmeliet, Peter1 aMoons, Lieve uhttp://view.ncbi.nlm.nih.gov/pubmed/1851169901805nas a2200217 4500008004100000245007400041210006900115260001400184300001400198490000700212520115600219100002201375700002501397700002101422700002101443700001801464700001801482700002001500700001801520856004901538 2006 eng d00aFunctional interaction of VEGF-C and VEGF-D with neuropilin receptors0 aFunctional interaction of VEGFC and VEGFD with neuropilin recept c2006/Jul/ a1462 - 720 v203 aLymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.1 aKärpänen, Terhi1 aHeckman, Caroline, A1 aKeskitalo, Salla1 aJeltsch, Michael1 aOllila, Hanna1 aNeufeld, Gera1 aTamagnone, Luca1 aAlitalo, Kari uhttp://view.ncbi.nlm.nih.gov/pubmed/1681612102694nas a2200313 4500008004100000245011900041210006900160260001400229300001300243490000800256520179900264100001802063700001602081700001702097700001502114700001902129700001802148700001702166700001302183700001502196700001902211700001502230700001402245700001802259700001702277700001502294700002202309856004902331 2000 eng d00aIntravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta0 aIntravascular adenovirusmediated VEGFC gene transfer reduces neo c2000/Oct/ a2262 - 80 v1023 aBACKGROUND: Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with lacZ adenovirus. Clinical-grade adenoviruses were used for the study. METHODS AND RESULTS: Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the lacZ-transfected control group was 0. 57+/-0.04. VEGF-C gene transfer reduced I/M to 0.38+/-0.02 (P:<0.05 versus lacZ group). I/M in VEGF-A-treated animals was 0.49+/-0.17 (P:=NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the lacZ group had an I/M of 0.73+/-0.16, the VEGF-C group 0.44+/-0.14, and the VEGF-A group 0. 63+/-0.21 (P:=NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between lacZ adenovirus and 0.9% saline-treated animals. CONCLUSIONS: Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.1 aHiltunen, M O1 aLaitinen, M1 aTurunen, M P1 aJeltsch, M1 aHartikainen, J1 aRissanen, T T1 aLaukkanen, J1 aNiemi, M1 aKossila, M1 aHäkkinen, T P1 aKivelä, A1 aEnholm, B1 aMansukoski, H1 aTurunen, A M1 aAlitalo, K1 aYlä-Herttuala, S uhttp://view.ncbi.nlm.nih.gov/pubmed/11056103