@article {701,
	title = {Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema},
	journal = {Molecular Genetics \& Genomic Medicine},
	volume = {00},
	year = {2020},
	month = {Feb-06-2022},
	pages = {e1389},
	issn = {2324-9269},
	doi = {10.1002/mgg3.1389},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/mgg3.1389},
	author = {Mukenge, Sylvain and Jha, Sawan K. and Catena, Marco and Manara, Elena and Lepp{\"a}nen, Veli-Matti and Lenti, Elisa and Negrini, Daniela and Bertelli, Matteo and Brendolan, Andrea and Jeltsch, Michael and Aldrighetti, Luca}
}
@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.}
}
@conference {625,
	title = {Inhibiton of VEGF-C-induced VEGFR-3 activity and lymphatic endothelial cell function by the tyrosine kinase inhibitor AZD2171},
	booktitle = {98th Annual Meeting of the American-Association-for-Cancer-Research},
	year = {2007},
	month = {2007///},
	publisher = {American Association for Cancer Research},
	organization = {American Association for Cancer Research},
	address = {Los Angeles, CA},
	abstract = {Solid tumors express a range of growth factors required to sustain their growth and promote their dissemination. Among these factors is vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors can prevent VEGF signaling activity by targeting the VEGF receptors and are an effective approach to impede tumor progression. The indole-ether quinazoline AZD2171 is a highly potent ATP-competitive inhibitor of VEGFR-2 (KDR) kinase, with additional activity against VEGFR-1 (Flt-1) and -3 (Flt-4), that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth (Wedge et al. Cancer Res 2005;65:4389-4400). For these studies we wished to further assess the ability of AZD2171 to inhibit VEGFR-3 and its associated functions. Upon binding its ligands VEGF-C or -D, VEGFR-3 becomes activated with the resulting signaling cascade eventually translated into increased proliferation, survival and migration of lymphatic and blood vascular endothelial cells. At concentrations of <=1 nM AZD2171 inhibited VEGFR-3 phosphorylation in porcine aortic endothelial cells selectively expressing the human receptor, and in human dermal microvascular endothelial cells (HDMVECs). In HDMVECs, AZD2171 prevented phosphorylation of signaling molecules downstream of VEGFR-2 and -3, ERK1/2, Akt and CREB, induced by the VEGFR-2 and -3-specific ligands VEGF-E and -C156S, respectively. Additionally, AZD2171 blocked VEGF-E- and -C156S-induced proliferation of both lymphatic and blood vascular endothelial cells at similar concentrations, and prevented ligand-induced endothelial cell cord formation in a Matrigel assay. The effects of AZD2171 on VEGF-C-induced lymphangiogenesis are currently being assessed in vivo. These studies, together with previous results, not only demonstrate that AZD2171 may be an effective means of preventing tumor progression by inhibition of VEGFR-2 activity and angiogenesis, but may also prevent further tumor spread by inhibiting VEGFR-3 activity},
	url = {http://dx.doi.org/10.1158/0008-5472.CAN-07-5809},
	author = {Heckman, Caroline A. and Holopainen, Tanja and Wirzenius, Maria and Keskitalo, Salla and Jeltsch, Michael and Wedge, Stephen R. and Jurgensmeier, Juliane M.}
}
@article {27,
	title = {Intrinsic versus microenvironmental regulation of lymphatic endothelial cell phenotype and function},
	journal = {FASEB J},
	volume = {17},
	year = {2003},
	month = {2003/Nov/},
	pages = {2006 - 13},
	abstract = {Vascular endothelial cells are characterized by a high degree of functional and phenotypic plasticity, which is controlled both by their pericellular microenvironment and their intracellular gene expression programs. To gain further insight into the mechanisms regulating the endothelial cell phenotype, we have compared the responses of lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BECs) to vascular endothelial growth factors (VEGFs). VEGFR-3-specific signals are sufficient for LEC but not BEC proliferation, as shown by the ability of the specific ligand VEGF-C156S to stimulate cell cycle entry only in LECs. On the other hand, we found that VEGFR-3 stimulation did not induce LEC cell shape changes typical of VEGFR-2-stimulated LECs, indicating receptor-specific differences in the cytoskeletal responses. Genes induced via VEGFR-2 also differed between BECs and LECs: angiopoietin-2 (Ang-2) was induced via VEGFR-2 in BECs and LECs, but the smooth muscle cell (SMC) chemoattractant BMP-2 was induced only in BECs. Both BECs and LECs were able to promote SMC chemotaxis, but contact with SMCs led to down-regulation of VEGFR-3 expression in BECs in a 3-dimensional coculture system. This was consistent with the finding that VEGFR-3 is down-regulated in vivo at sites of endothelial cell-pericyte/smooth muscle cell contacts. Collectively, these data show intrinsic cell-specific differences of BEC and LEC responses to VEGFs and identify a pericellular regulatory mechanism for VEGFR-3 down-regulation in endothelial cells.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/14597670},
	author = {Veikkola, Tanja and Lohela, Marja and Ikenberg, Kristian and M{\"a}kinen, Taija and Korff, Thomas and Saaristo, Anne and Petrova, Tatania and Jeltsch, Michael and Augustin, Hellmut G and Alitalo, Kari}
}
@article {20,
	title = {Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta},
	journal = {Circulation},
	volume = {102},
	year = {2000},
	month = {2000/Oct/},
	pages = {2262 - 8},
	abstract = {BACKGROUND: 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.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/11056103},
	author = {Hiltunen, M O and Laitinen, M and Turunen, M P and Jeltsch, M and Hartikainen, J and Rissanen, T T and Laukkanen, J and Niemi, M and Kossila, M and H{\"a}kkinen, T P and Kivel{\"a}, A and Enholm, B and Mansukoski, H and Turunen, A M and Alitalo, K and Yl{\"a}-Herttuala, S}
}
