FrzA, a secreted frizzled related protein, induced angiogenic response.
BACKGROUND
The secreted frizzled related proteins (sFRP) are soluble proteins thought to interfere with the Wnt signaling. Our group previously demonstrated that one of these members, sFRP-1/FrzA, is strongly expressed during early phases of the vascularization process in embryonic vasculature and in the endothelium of arteries and capillaries in adults and modulated vascular cell proliferation.


RESULTS
Analysis of the expression of sFRP-1 during cyclic ovarian angiogenesis revealed that sFRP-1 is expressed during the formation of neovessels and becomes undetectable when the vasculature is fully maturated. We then studied the role of FrzA in several distinct angiogenic models. FrzA induced angiogenesis in a chick chorioallantoic membrane model. Moreover, gene transfer of AdFrzA in grafted mesenchymal and glioma cells increased vessel density and tumor growth. FrzA induced formation of vessels, which were enlarged, longer, and appeared to be more mature compared with vessels formed under control treatments. In vitro, FrzA increased migration and tube formation of endothelial cells and seemed to protect them from apoptosis. FrzA-angiogenic effect in vitro was independent of vascular endothelial growth factor, fibroblast growth factor-2, or angiopiotin-1 induction and Akt activation. In contrast, FrzA decreased glycogen synthase kinase-3 phosphorylation.


CONCLUSIONS
These results showed that FrzA has proangiogenic effects and suggest that Wnt signaling may be involved in normal differentiation as well as in the pathological development of vasculature.
Dufourcq
Pascale
P
Inserm U441, Pessac, France. pascale.dufourcq@biophar.u-bordeaux2.fr
Couffinhal
Thierry
T
Ezan
Jérome
J
Barandon
Laurent
L
Moreau
Catherine
C
Daret
Danièle
D
Duplàa
Cécile
C
D000482:Allantois / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010053:Ovary / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D016228:Endothelial Growth Factors; D038362:Glycogen Synthase Kinase 3; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008222:Lymphokines; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099274:Frizzled-Related Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C485539:Sfrp1 protein, mouse; C494918:AKT1 protein, human