@article {693,
	title = {KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D},
	journal = {eLife},
	volume = {8},
	year = {2019},
	month = {2019/05/17/},
	pages = {e44478},
	abstract = {Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, e.g. in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAMTS3, KLK3 is the third protease shown to activate VEGF-C. Since differently activated VEGF-Cs are characterized by successively shorter N-terminal helices, we created an even shorter hypothetical form, which showed preferential binding to VEGFR-3. Using mass spectrometric analysis of the isolated VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.},
	keywords = {cancer biology, Cathepsin D, kallikrein-related peptidases, KLK3/PSA, Lymphangiogenesis, mouse, VEGF-C, VEGF-D},
	isbn = {2050-084X},
	url = {https://elifesciences.org/articles/44478},
	author = {Jha, Sawan Kumar and Rauniyar, Khushbu and Chronowska, Ewa and Mattonet, Kenny and Maina, Eunice Wairimu and Koistinen, Hannu and Stenman, Ulf-H{\r a}kan and Alitalo, Kari and Jeltsch, Michael}
}
@article {39,
	title = {Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development},
	journal = {Genes Dev},
	volume = {24},
	year = {2010},
	month = {2010/May/},
	pages = {875 - 80},
	abstract = {The 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.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/20439428},
	author = {Saharinen, Pipsa and Helotera, Hanna and Miettinen, Juho and Norrmen, Camilla and D{\textquoteright}Amico, Gabriela and Jeltsch, Michael and Langenberg, Tobias and Vandevelde, Wouter and Ny, Annelii and Dewerchin, Mieke and Carmeliet, Peter and Alitalo, Kari}
}
@article {41,
	title = {Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis},
	journal = {PLoS ONE},
	volume = {5},
	year = {2010},
	month = {2010//},
	pages = {e14109},
	abstract = {BACKGROUND: The family of vascular endothelial growth factors (VEGF) contains key regulators of blood and lymph vessel development, including VEGF-A, -B, -C, -D, and placental growth factor. The role of VEGF-B during physiological or pathological angiogenesis has not yet been conclusively delineated. Herein, we investigate the function of VEGF-B by the generation of mouse models of cancer with transgenic expression of VEGF-B or homozygous deletion of Vegfb. METHODOLOGY/PRINCIPAL FINDINGS: Ectopic expression of VEGF-B in the insulin-producing β-cells of the pancreas did not alter the abundance or architecture of the islets of Langerhans. The vasculature from transgenic mice exhibited a dilated morphology, but was of similar density as that of wildtype mice. Unexpectedly, we found that transgenic expression of VEGF-B in the RIP1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis retarded tumor growth. Conversely, RIP1-Tag2 mice deficient for Vegfb presented with larger tumors. No differences in vascular density, perfusion or immune cell infiltration upon altered Vegfb gene dosage were noted. However, VEGF-B acted to increase blood vessel diameter both in normal pancreatic islets and in RIP1-Tag2 tumors. CONCLUSIONS/SIGNIFICANCE: Taken together, our results illustrate the differences in biological function between members of the VEGF family, and highlight the necessity of in-depth functional studies of VEGF-B to fully understand the effects of VEGFR-1 inhibitors currently used in the clinic.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/21124841},
	author = {Albrecht, Imke and Kopfstein, Lucie and Strittmatter, Karin and Schomber, Tibor and Falkevall, Annelie and Hagberg, Carolina E and Lorentz, Pascal and Jeltsch, Michael and Alitalo, Kari and Eriksson, Ulf and Christofori, Gerhard and Pietras, Kristian}
}
@article {43,
	title = {Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation},
	journal = {Circulation},
	volume = {122},
	year = {2010},
	month = {2010/Oct/},
	pages = {1725 - 33},
	abstract = {BACKGROUND: Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood. METHODS AND RESULTS: Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B(167) isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment. CONCLUSIONS: VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B-induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B-induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/20937974},
	author = {Bry, Maija and Kivel{\"a}, Riikka and Holopainen, Tanja and Anisimov, Andrey and Tammela, Tuomas and Soronen, Jarkko and Silvola, Johanna and Saraste, Antti and Jeltsch, Michael and Korpisalo, Petra and Carmeliet, Peter and Lemstr{\"o}m, Karl B and Shibuya, Masabumi and Yl{\"a}-Herttuala, Seppo and Alhonen, Leena and Mervaala, Eero and Andersson, Leif C and Knuuti, Juhani and Alitalo, Kari}
}
@article {36,
	title = {Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium},
	journal = {Arterioscler Thromb Vasc Biol},
	volume = {28},
	year = {2008},
	month = {2008/Sep/},
	pages = {1614 - 20},
	abstract = {OBJECTIVE: 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.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/18511699},
	author = {Li, Xuri and Tjwa, Marc and Van Hove, Inge and Enholm, Berndt and Neven, Elke and Paavonen, Karri and Jeltsch, Michael and Juan, Toni Diez and Sievers, Richard E and Chorianopoulos, Emmanuel and Wada, Hiromichi and Vanwildemeersch, Maarten and Noel, Agnes and Foidart, Jean-Michel and Springer, Matthew L and von Degenfeld, Georges and Dewerchin, Mieke and Blau, Helen M and Alitalo, Kari and Eriksson, Ulf and Carmeliet, Peter and Moons, Lieve}
}
@article {23,
	title = {Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis},
	journal = {EMBO J},
	volume = {20},
	year = {2001},
	month = {2001/Feb/},
	pages = {672 - 82},
	abstract = {Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/11179212},
	author = {Mandriota, S J and Jussila, L and Jeltsch, M and Compagni, A and Baetens, D and Prevo, R and Banerji, S and Huarte, J and Montesano, R and Jackson, D G and Orci, L and Alitalo, K and Christofori, G and Pepper, M S}
}
@article {13,
	title = {Genomic organization of human and mouse genes for vascular endothelial growth factor C},
	journal = {J Biol Chem},
	volume = {272},
	year = {1997},
	month = {1997/Oct/},
	pages = {25176 - 83},
	abstract = {We report here the cloning and characterization of human and mouse genes for vascular endothelial growth factor C (VEGF-C), a newly isolated member of the vascular endothelial growth factor/platelet-derived growth factor (VEGF/PDGF) family. Both VEGF-C genes comprise over 40 kilobase pairs of genomic DNA and consist of seven exons, all containing coding sequences. The VEGF homology domain of VEGF-C is encoded by exons 3 and 4. Exons 5 and 7 encode cysteine-rich motifs of the type C6C10CRC, and exon 6 encodes additional C10CXCXC motifs typical of a silk protein. A putative alternatively spliced rare RNA form lacking exon 4 was identified in human fibrosarcoma cells, and a major transcription start site was located in the human VEGF-C gene 523 base pairs upstream of the translation initiation codon. The upstream promoter sequences contain conserved putative binding sites for Sp-1, AP-2, and NF-kappaB transcription factors but no TATA box, and they show promoter activity when transfected into cells. The VEGF-C gene structure is thus assembled from exons encoding propeptides and distinct cysteine-rich domains in addition to the VEGF homology domain, and it shows both similarities and distinct differences in comparison with other members of the VEGF/PDGF gene family.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/9312130},
	author = {Chilov, D and Kukk, E and Taira, S and Jeltsch, M and Kaukonen, J and Palotie, A and Joukov, V and Alitalo, K}
}
@article {14,
	title = {Proteolytic processing regulates receptor specificity and activity of VEGF-C},
	journal = {EMBO J},
	volume = {16},
	year = {1997},
	month = {1997/Jul/},
	pages = {3898 - 911},
	abstract = {The recently identified vascular endothelial growth factor C (VEGF-C) belongs to the platelet-derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial-specific receptor tyrosine kinases VEGFR-3 and VEGFR-2. The VEGF homology domain spans only about one-third of the cysteine-rich VEGF-C precursor. Here we have analysed the role of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C. The stepwise proteolytic processing of VEGF-C generated several VEGF-C forms with increased activity towards VEGFR-3, but only the fully processed VEGF-C could activate VEGFR-2. Recombinant {\textquoteright}mature{\textquoteright} VEGF-C made in yeast bound VEGFR-3 (K[D] = 135 pM) and VEGFR-2 (K[D] = 410 pM) and activated these receptors. Like VEGF, mature VEGF-C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF-C formed mostly non-covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF-C activity, and reveal novel structure-function relationships in the PDGF/VEGF family.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/9233800},
	author = {Joukov, V and Sorsa, T and Kumar, V and Jeltsch, M and Claesson-Welsh, L and Cao, Y and Saksela, O and Kalkkinen, N and Alitalo, K}
}
@article {11,
	title = {VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane},
	journal = {Dev Biol},
	volume = {188},
	year = {1997},
	month = {1997/Aug/},
	pages = {96 - 109},
	abstract = {The 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.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/9245515},
	author = {Oh, S J and Jeltsch, M M and Birkenh{\"a}ger, R and McCarthy, J E and Weich, H A and Christ, B and Alitalo, K and Wilting, J}
}
