00566nas a2200157   4500008004100000022001400041245010100055210006900156260001600225100002100241700002300262700001900285700002500304700002100329856005800350       2024                        eng d  a1464-793100aThe relationship between the secondary vascular system and the lymphatic vascular system in fish0 arelationship between the secondary vascular system and the lymph  cApr-06-20261 aPanara, Virginia1 aVaraliová, Zuzana1 aWilting, Jörg1 aKoltowska, Katarzyna1 aJeltsch, Michael  uhttps://onlinelibrary.wiley.com/doi/10.1111/brv.1311402098nas 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/1851169902705nas a2200229   4500008004100000245014300041210006900184260001400253300001400267490000700281520193200288100002502220700002202245700002102267700002102288700002102309700002602330700002202356700003002378700001802408856004902426       2008                        eng d00aThe tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis0 atyrosine kinase inhibitor cediranib blocks ligandinduced vascula  c2008/Jun/  a4754 - 620 v683 aSolid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of </=1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S-induced and VEGF-E-induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E-expressing and VEGF-C156S-expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C-expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis.1 aHeckman, Caroline, A1 aHolopainen, Tanja1 aWirzenius, Maria1 aKeskitalo, Salla1 aJeltsch, Michael1 aYlä-Herttuala, Seppo1 aWedge, Stephen, R1 aJürgensmeier, Juliane, M1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/1855952201736nas a2200169   4500008004100000245005000041210005000091260001400141300001200155490000800167520126400175100002101439700002001460700001801480700001901498856004901517       2003                        eng d00aGenesis and pathogenesis of lymphatic vessels0 aGenesis and pathogenesis of lymphatic vessels  c2003/Oct/  a69 - 840 v3143 aThe lymphatic system is generally regarded as supplementary to the blood vascular system, in that it transports interstitial fluid, macromolecules, and immune cells back into the blood. However, in insects, the open hemolymphatic (or lymphohematic) system ensures the circulation of immune cells and interstitial fluid through the body. The Drosophila homolog of the mammalian vascular endothelial growth factor receptor (VEGFR) gene family is expressed in hemocytes, suggesting a close relationship to the endothelium that develops later in phylogeny. Lymph hearts are typical organs for the propulsion of lymph in lower vertebrates and are still transiently present in birds. The lymphatic endothelial marker VEGFR-3 is transiently expressed in embryonic blood vessels and is crucial for their development. We therefore regard the question of whether the blood vascular system or the lymphatic system is primary or secondary as open. Future molecular comparisons should be performed without any bias based on the current prevalence of the blood vascular system over the lymphatic system. Here, we give an overview of the structure, function, and development of the lymphatics, with special emphasis on the recently discovered lymphangiogenic growth factors.1 aJeltsch, Michael1 aTammela, Tuomas1 aAlitalo, Kari1 aWilting, Jörg  uhttp://view.ncbi.nlm.nih.gov/pubmed/1294236201686nas a2200217   4500008004100000245013700041210006900178260001400247300001300261490000700274520102000281100001501301700001501316700001201331700001601343700001401359700001501373700001501388700001701403856004801420       1998                        eng d00aVascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)0 aVascular endothelial growth factor D VEGFD is a ligand for the t  c1998/Jan/  a548 - 530 v953 aWe have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.1 aAchen, M G1 aJeltsch, M1 aKukk, E1 aMäkinen, T1 aVitali, A1 aWilks, A F1 aAlitalo, K1 aStacker, S A  uhttp://view.ncbi.nlm.nih.gov/pubmed/943522902815nas a2200217   4500008004100000245013100041210006900172260001400241300001300255490000800268520214700276100001202423700001702435700002002452700001802472700001502490700001402505700001502519700001502534856004802549       1997                        eng d00aVEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane0 aVEGF and VEGFC specific induction of angiogenesis and lymphangio  c1997/Aug/  a96 - 1090 v1883 aThe lymphangiogenic potency of endothelial growth factors has not been studied to date. This is partially due to the lack of in vivo lymphangiogenesis assays. We have studied the lymphatics of differentiated avian chorioallantoic membrane (CAM) using microinjection of Mercox resin, semi- and ultrathin sectioning, immunohistochemical detection of fibronectin and alpha-smooth muscle actin, and in situ hybridization with VEGFR-2 and VEGFR-3 probes. CAM is drained by lymphatic vessels which are arranged in a regular pattern. Arterioles and arteries are accompanied by a pair of interconnected lymphatics and form a plexus around bigger arteries. Veins are also associated with lymphatics, particularly larger veins, which are surrounded by a lymphatic plexus. The lymphatics are characterized by an extremely thin endothelial lining, pores, and the absence of a basal lamina. Patches of the extracellular matrix can be stained with an antibody against fibronectin. Lymphatic endothelial cells of differentiated CAM show ultrastructural features of this cell type. CAM lymphatics do not possess mediae. In contrast, the lymphatic trunks of the umbilical stalk are invested by a single but discontinuous layer of smooth muscle cells. CAM lymphatics express VEGFR-2 and VEGFR-3. Both the regular pattern and the typical structure of these lymphatics suggest that CAM is a suitable site to study the in vivo effects of potential lymphangiogenic factors. We have studied the effects of VEGF homo- and heterodimers, VEGF/PlGF heterodimers, and PlGF and VEGF-C homodimers on Day 13 CAM. All the growth factors containing at least one VEGF chain are angiogenic but do not induce lymphangiogenesis. PlGF-1 and PlGF-2 are neither angiogenic nor lymphangiogenic. VEGF-C is the first lymphangiogenic factor and seems to be highly chemoattractive for lymphatic endothelial cells. It induces proliferation of lymphatic endothelial cells and development of new lymphatic sinuses which are directed immediately beneath the chorionic epithelium. Our studies show that VEGF and VEGF-C are specific angiogenic and lymphangiogenic growth factors, respectively.1 aOh, S J1 aJeltsch, M M1 aBirkenhäger, R1 aMcCarthy, J E1 aWeich, H A1 aChrist, B1 aAlitalo, K1 aWilting, J  uhttp://view.ncbi.nlm.nih.gov/pubmed/9245515