@article {505,
	title = {Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts},
	journal = {American Journal of Transplantation},
	volume = {16},
	year = {2015},
	month = {12/2015},
	pages = {1160-1172},
	abstract = {Organ 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{\textendash}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.},
	doi = {10.1111/ajt.13564},
	url = {http://onlinelibrary.wiley.com/doi/10.1111/ajt.13564/abstract},
	author = {Dashkevich, A. and Raissadati, A. and Syrj{\"a}l{\"a}, S. O. and Zarkada, G. and Ker{\"a}nen, M. A. I. and Tuuminen, R. and Krebs, R. and Anisimov, A. and Jeltsch, M. and Lepp{\"a}nen, V.-M. and Alitalo, K. and Nyk{\"a}nen, A. I. and Lemstr{\"o}m, K. B.}
}
@article {426,
	title = {The basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands},
	journal = {Sci Signal},
	volume = {6},
	year = {2013},
	month = {2013},
	pages = {ra52},
	abstract = {<p>Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development through VEGF receptors (VEGFRs). The VEGFR immunoglobulin homology domain 2 (D2) is critical for ligand binding, and D3 provides additional interaction sites. VEGF-B and placenta growth factor (PlGF) bind to VEGFR-1 with high affinity, but only PlGF is angiogenic in most tissues. We show that VEGF-B, unlike other VEGFs, did not require D3 interactions for high-affinity binding. VEGF-B with a PlGF-derived L1 loop (B-L1(P)) stimulated VEGFR-1 activity, whereas PlGF with a VEGF-B-derived L1 loop (P-L1(B)) did not. Unlike P-L1(B) and VEGF-B, B-L1(P) and PlGF were also angiogenic in mouse skeletal muscle. Furthermore, B-L1(P) also bound to VEGFR-2 and activated downstream signaling. These results establish a role for L1-mediated D3 interactions in VEGFR activation in endothelial cells and indicate that VEGF-B is a high-affinity VEGFR-1 ligand that, unlike PlGF, cannot efficiently induce signaling downstream of VEGFR-1.</p>},
	keywords = {PlGF, receptor tyrosine kinase, Signal Transduction, VEGF-B, VEGFR-1},
	issn = {1937-9145},
	doi = {10.1126/scisignal.2003905},
	author = {Anisimov, Andrey and Lepp{\"a}nen, Veli-Matti and Tvorogov, Denis and Zarkada, Georgia and Jeltsch, Michael and Holopainen, Tanja and Kaijalainen, Seppo and Alitalo, Kari}
}
@article {425,
	title = {A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development.},
	journal = {Development},
	volume = {140},
	year = {2013},
	month = {2013 Apr},
	pages = {1497-506},
	abstract = {<p>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.</p>},
	keywords = {Alleles, Animals, Animals, Genetically Modified, Autocrine Communication, Blood Vessels, Cell Movement, Codon, Nonsense, Embryo, Nonmammalian, Female, Lymphatic System, Mice, Mice, Knockout, Neovascularization, Physiologic, Paracrine Communication, Protein Isoforms, Signal Transduction, Vascular Endothelial Growth Factor C, Zebrafish, Zebrafish Proteins},
	issn = {1477-9129},
	doi = {10.1242/dev.084152},
	author = {Villefranc, Jacques A and Nicoli, Stefania and Bentley, Katie and Jeltsch, Michael and Zarkada, Georgia and Moore, John C and Gerhardt, Holger and Alitalo, Kari and Lawson, Nathan D}
}
@article {42,
	title = {Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization},
	journal = {Cancer Cell},
	volume = {18},
	year = {2010},
	month = {2010/Dec/},
	pages = {630 - 40},
	abstract = {Antibodies that block vascular endothelial growth factor (VEGF) have become an integral part of antiangiogenic tumor therapy, and antibodies targeting other VEGFs and receptors (VEGFRs) are in clinical trials. Typically receptor-blocking antibodies are targeted to the VEGFR ligand-binding site. Here we describe a monoclonal antibody that inhibits VEGFR-3 homodimer and VEGFR-3/VEGFR-2 heterodimer formation, signal transduction, as well as ligand-induced migration and sprouting of microvascular endothelial cells. Importantly, we show that combined use of antibodies blocking ligand binding and receptor dimerization improves VEGFR inhibition and results in stronger inhibition of endothelial sprouting and vascular network formation in vivo. These results suggest that receptor dimerization inhibitors could be used to enhance antiangiogenic activity of antibodies blocking ligand binding in tumor therapy.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/21130043},
	author = {Tvorogov, Denis and Anisimov, Andrey and Zheng, Wei and Lepp{\"a}nen, Veli-Matti and Tammela, Tuomas and Laurinavicius, Simonas and Holnthoner, Wolfgang and Heloter{\"a}, Hanna and Holopainen, Tanja and Jeltsch, Michael and Kalkkinen, Nisse and Lankinen, Hilkka and Ojala, P{\"a}ivi M and Alitalo, Kari}
}
