Published online before print January 22, 2004, doi: 10.1161/01.RES.0000118600.91698.BB
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Submitted on December 2, 2002
Revised on January 12, 2004
Accepted on January 13, 2004
Comparative Evaluation of FGF-2-, VEGF-A-, and VEGF-C-Induced Angiogenesis, Lymphangiogenesis, Vascular Fenestrations, and Permeability
Renhai Cao ;
From the Microbiology and Tumor Biology Center (R.C., A.E., Y.C.) Karolinska Institutet, Stockholm, Sweden; Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research (H.K., K.A.), Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; and Department of Cell and Molecular Biology (J.T.), Karolinska Institutet, Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: yihai.cao{at}mtc.ki.se.
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.
Key words: angiogenesis • lymphangiogenesis • endothelial fenestrations • vascular permeability
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