00911nas 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-Marrow02729nas a2200349   4500008004100000245015500041210006900196260001400265300001400279490000800293520163900301100001501940700002001955700002201975700002101997700002002018700002002038700002102058700001902079700002102098700002102119700002102140700002302161700002202184700002602206700001902232700001902251700002302270700001902293700001802312856004902330       2010                        eng d00aVascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation0 aVascular endothelial growth factorB acts as a coronary growth fa  c2010/Oct/  a1725 - 330 v1223 aBACKGROUND: 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.1 aBry, Maija1 aKivelä, Riikka1 aHolopainen, Tanja1 aAnisimov, Andrey1 aTammela, Tuomas1 aSoronen, Jarkko1 aSilvola, Johanna1 aSaraste, Antti1 aJeltsch, Michael1 aKorpisalo, Petra1 aCarmeliet, Peter1 aLemström, Karl, B1 aShibuya, Masabumi1 aYlä-Herttuala, Seppo1 aAlhonen, Leena1 aMervaala, Eero1 aAndersson, Leif, C1 aKnuuti, Juhani1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/2093797401519nas a2200193   4500008004100000245014600041210006900187260001400256300001500270490000800285520086800293100002101161700002001182700002001202700001501222700002101237700001801258856004901276       2006                        eng d00aVascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns0 aVascular endothelial growth factor VEGFVEGFC mosaic molecules re  c2006/Apr/  a12187 - 950 v2813 aVascular endothelial growth factors (VEGFs) and their receptors play key roles in angiogenesis and lymphangiogenesis. VEGF activates VEGF receptor-1 (VEGFR-1) and VEGFR-2, whereas VEGF-C activates VEGFR-2 and VEGFR-3. We have created a library of VEGF/VEGF-C mosaic molecules that contains factors with novel receptor binding profiles, notably proteins binding to all three VEGF receptors ("super-VEGFs"). The analyzed super-VEGFs show both angiogenic and lymphangiogenic effects in vivo, although weaker than the parental molecules. The composition of the VEGFR-3 binding molecules and scanning mutagenesis revealed determinants of receptor binding and specificity. VEGFR-2 and VEGFR-3 showed striking differences in their requirements for VEGF-C binding; extracellular domain 2 of VEGFR-2 was sufficient, whereas in VEGFR-3, both domains 1 and 2 were necessary.1 aJeltsch, Michael1 aKarpanen, Terhi1 aStrandin, Tomas1 aAho, Kukka1 aLankinen, Hilkka1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/1650548900372nas a2200133   4500008004100000245001900041210001900060250000700079260001000086100002100096700001800117710001600135856008700151       2006                        eng d00aVEGF Receptors0 aVEGF Receptors  a5.  bSigma1 aJeltsch, Michael1 aAlitalo, Kari1 aWatling, K.  uhttp://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook.html02358nas a2200241   4500008004100000245016500041210006900206260001400275300001400289490000700303520155700310100001501867700001901882700002001901700002101921700002201942700002501964700002001989700001702009700002302026700001802049856004902067       2005                        eng d00aVascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels0 aVascular endothelial cell growth factor receptor 3mediated activ  c2005/Jun/  a4739 - 460 v653 aLymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to promote lymphatic metastasis by inducing tumor-associated lymphangiogenesis. In this study, we have investigated how tumor cells gain access into lymphatic vessels and at what stage tumor cells initiate metastasis. We show that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis. A significant increase in lymphatic vessel growth occurred between 2 and 3 weeks after tumor xenotransplantation, and lymph node metastasis occurred at the same stage. These processes were blocked dose-dependently by inhibition of VEGF receptor 3 (VEGFR-3) signaling by systemic delivery of a soluble VEGFR-3-immunoglobulin (Ig) fusion protein via adenoviral or adeno-associated viral vectors. However, VEGFR-3-Ig did not suppress lymph node metastasis when the treatment was started at a later stage after the tumor cells had already spread out, suggesting that tumor cell entry into lymphatic vessels is a key step during tumor dissemination via the lymphatics. Whereas lymphangiogenesis and lymph node metastasis were significantly inhibited by VEGFR-3-Ig, some tumor cells were still detected in the lymph nodes in some of the treated mice. This indicates that complete blockade of lymphatic metastasis may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.1 aHe, Yulong1 aRajantie, Iiro1 aPajusola, Katri1 aJeltsch, Michael1 aHolopainen, Tanja1 aYla-Herttuala, Seppo1 aHarding, Thomas1 aJooss, Karin1 aTakahashi, Takashi1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/1593029201674nas a2200265   4500008004100000245011900041210006900160260001400229300001200243490000600255520085100261100002601112700001701138700001801155700001901173700001901192700002401211700002101235700002201256700001901278700002001297700002401317700001801341856004901359       2004                        eng d00aVascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins0 aVascular endothelial growth factor C is required for sprouting o  c2004/Jan/  a74 - 800 v53 aLymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development.1 aKarkkainen, Marika, J1 aHaiko, Paula1 aSainio, Kirsi1 aPartanen, Juha1 aTaipale, Jussi1 aPetrova, Tatiana, V1 aJeltsch, Michael1 aJackson, David, G1 aTalikka, Marja1 aRauvala, Heikki1 aBetsholtz, Christer1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/1463464601908nas a2200253   4500008004100000245007800041210006900119260001400188300001400202490000800216520113900224100002101363700002101384700002201405700002501427700002201452700002501474700002101499700002601520700001801546700001701564700002401581856004901605       2003                        eng d00aVEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia0 aVEGF guides angiogenic sprouting utilizing endothelial tip cell   c2003/Jun/  a1163 - 770 v1613 aVascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.1 aGerhardt, Holger1 aGolding, Matthew1 aFruttiger, Marcus1 aRuhrberg, Christiana1 aLundkvist, Andrea1 aAbramsson, Alexandra1 aJeltsch, Michael1 aMitchell, Christopher1 aAlitalo, Kari1 aShima, David1 aBetsholtz, Christer  uhttp://view.ncbi.nlm.nih.gov/pubmed/1281070002637nas a2200109   4500008004500000245004200045210004100087490001500128520230100143100002102444856006202465       2002                        Engldsh  00aVEGFR-3 Ligands and Lymphangiogenesis0 aVEGFR3 Ligands and Lymphangiogenesis0 vPhD Thesis3 aMost of us have seen their own blood at one or the other time. The occasion might have been
a small accident or in unfortunate cases a severe blood loss caused by a major injury. We also
can feel our heart beating and the resulting pressure wave, the pulse. The existence of the car-
diovascular system is obvious to us. Unlike the cardiovascular system, the lymphatic system
has, until recently, escaped notable attention not only by the laymen, but also by the scientific
community. It is unclear why the lymphatic system originally developed in higher vertebrates.
Now, its main function seems to be to collect fluid that has leaked from the blood vessels and
to return it into the cardiovascular system. Much of our knowledge about the development and
structure of the lymphatic system is of considerable age, and it has been said that there has not
been any progress in our understanding since the fine structure of the lymphatics was described
with the introduction of the electron microscope.
Vascular endothelial growth factor (VEGF) is the principal direct inducer of blood vessel
growth, but it does not promote the growth of lymphatic vessels. This study demonstrates for
the first time specific lymphangiogenesis as a response to the VEGF homologue VEGF-C.
Overexpression of full length VEGF-C under the keratin-14 promoter in the skin of transgenic
mice caused a proliferation of the lymphatic endothelium and lymphatic vessel enlargement. In
the chorioallantoic membrane assay, the mature form of VEGF-C was also largely specific for
lymphatic endothelial cells. A newly discovered close homologue of VEGF-C, VEGF-D was
then shown to have the same receptor-binding pattern as VEGF-C.
Contrary to the interaction of VEGF with its receptors, VEGF-C interaction with VEGFR-3 has
not been analyzed at the molecular level. The structural determinants of VEGFR-3 binding were
characterized in relation to VEGF using a non-random family shuffling approach with VEGF
and VEGF-C as parent molecules. This approach led to the identification of VEGF/VEGF-C
mosaic molecules that showed novel receptor binding profiles and a panel of these molecules
was used to delineate the requirements of specific receptors in the induction of angiogenesis
versus lymphangiogenesis.1 aJeltsch, Michael  uhttp://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/jeltsch