© 1997 American Heart Association, Inc.
Articles |
Basic Fibroblast Growth Factor–Induced Angiogenic Phenotype in Mouse Endothelium
A Study of Aortic and Microvascular Endothelial Cell Lines
From the Unit of General Pathology and Immunology (M.B., E.E.N., P.Dell'E., M.R., M.P.) and Unit of Histology (M.P.M.-T., S.P.), Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy; Laboratory of Developmental Biology (R.A.), Department of Zoology, University of Wisconsin, Madison; Unit of Immunopathology (L.P.R.), Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy; and Institute of Biomedical Sciences (L.P.), University of Ancona, Italy.
Correspondence to Marco Presta, General Pathology, Department of Biomedical Sciences and Biotechnology, via Valsabbina 19, 25123 Brescia, Italy. E-mail presta{at}master.cci.unibs.it
Abstract The mouse is the most commonly used species
for in vivo studies on angiogenesis related to tumor development. Yet,
to the best of our knowledge, very few reports on the in vitro
interaction of the angiogenic basic fibroblast growth factor (bFGF)
with mouse endothelial cells are available. Three mouse endothelial
cell lines originated from aorta (MAECs), brain capillaries (MBECs),
and heart capillaries (MHECs) were characterized for endothelial
phenotypic markers, in vivo tumorigenic activity, and the capacity to
respond in vitro to bFGF. These cells express angiotensin-converting
enzyme, acetylated LDL receptor, constitutive endothelial nitric oxide
synthase, and vascular cell adhesion molecule-1 and bind
Griffonia simplicifolia-I lectin. When injected
subcutaneously in nude mice, MAECs induced the appearance of
slow-growing vascular lesions reminiscent of epithelioid
hemangioendothelioma, whereas MBEC xenografts grew rapidly, showing
Kaposi's sarcoma–like morphological features. No lesions were induced
by injection of MHECs. MAECs, MBECs, and MHECs expressed both
low-affinity heparan sulfate bFGF-binding sites and high-affinity
tyrosine kinase receptors (FGFRs) on their surfaces. In particular,
MAECs expressed FGFR-2/bek mRNA, whereas microvascular MBECs
and MHECs expressed FGFR-1/flg mRNA. Accordingly, bFGF
induced a mitogenic response and the phosphorylation of extracellular
signal-regulated kinase-2 in all the cell lines. In contrast,
upregulation of urokinase-type plasminogen activator expression was
observed in bFGF–treated microvascular MBECs and MHECs but not in
MAECs. Also, bFGF–treated MBECs and MHECs but not MAECs invaded a
three-dimensional fibrin gel and formed hollow, capillary-like
structures. The relevance of the modifications of the fibrinolytic
balance of mouse microvascular endothelium in bFGF–induced
angiogenesis was validated in vivo by a gelatin-sponge assay in which
the plasmin inhibitors tranexamic acid and 
-aminocaproic acid given
to mice in the drinking water inhibited neovascularization induced by
the growth factor. In conclusion, differences in response to bFGF exist
between large-vessel MAECs and microvascular MBECs and MHECs. Both in
vitro and in vivo data point to a role of the profibrinolytic phenotype
induced by bFGF in microvascular endothelial cells during mouse
angiogenesis. Our observations make these endothelial cell lines
suitable for further studies on mouse endothelium during angiogenesis
and in angioproliferative diseases.
Key Words: angiogenesis • endothelium • mouse • basic fibroblast growth factor • plasminogen activators
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