Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability.
Several endothelial growth factors induce both blood and lymphatic angiogenesis. However, a systematic comparative study of the impact of these factors on vascular morphology and function has been lacking. In this study, we report a quantitative analysis of the structure and macromolecular permeability of FGF-2-, VEGF-A-, and VEGF-C-induced blood and lymphatic vessels. Our results show that VEGF-A stimulated formation of disorganized, nascent vasculatures as a result of fusion of blood capillaries into premature plexuses with only a few lymphatic vessels. Ultrastructural analysis revealed that VEGF-A-induced blood vessels contained high numbers of endothelial fenestrations that mediated high permeability to ferritin, whereas the FGF-2-induced blood vessels lacked vascular fenestrations and showed only little leakage of ferritin. VEGF-C induced approximately equal amounts of blood and lymphatic capillaries with endothelial fenestrations present only on blood capillaries, mediating a medium level of ferritin leakage into the perivascular space. No endothelial fenestrations were found in FGF-2-, VEGF-A-, or VEGF-C-induced lymphatic vessels. These findings highlight the structural and functional differences between blood and lymphatic vessels induced by FGF-2, VEGF-A, and VEGF-C. Such information is important to consider in development of novel therapeutic strategies using these angiogenic factors.
Cao
Renhai
R
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
Eriksson
Anna
A
Kubo
Hajime
H
Alitalo
Kari
K
Cao
Yihai
Y
Thyberg
Johan
J
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000648:ultrastructure*; D002199:Capillary Permeability / Q000187:drug effects*; D021941:Caveolae / Q000502:physiology; D016510:Corneal Neovascularization; D004343:Drug Implants; D004730:Endothelium, Vascular / Q000648:ultrastructure*; D005293:Ferritins / Q000493:pharmacokinetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D042583:Lymphangiogenesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology*
D004343:Drug Implants; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; C467486:VEGFC protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D016222:Fibroblast Growth Factor 2; D005293:Ferritins