Basic Fibroblast Growth Factor–Induced Angiogenic Phenotype in Mouse Endothelium
- 1 March 1997
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 17 (3), 454-464
- https://doi.org/10.1161/01.atv.17.3.454
Abstract
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 ε-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.Keywords
This publication has 40 references indexed in Scilit:
- Interaction of high‐molecular‐weight basic fibroblast growth factor with endothelium: Biological activity and intracellular fate of human recombinant Mr 24,000 bFGFJournal of Cellular Physiology, 1994
- Distinct Role of 2-O-, N-, and 6-O-Sulfate Groups of Heparin in the Formation of the Ternary Complex with Basic Fibroblast Growth Factor and Soluble FGF Receptor-1Biochemical and Biophysical Research Communications, 1994
- Genomic analysis and expression patterns reveal distinct genes for endothelial and brain nitric oxide synthase.Hypertension, 1993
- Basic fibroblast growth factor increases junctional communication and connexin 43 expression in microvascular endothelial cellsJournal of Cellular Physiology, 1992
- Structure-function relationship of basic fibroblast growth factor: Site-directed mutagenesis of a putative heparin-binding and receptor-binding regionBiochemical and Biophysical Research Communications, 1992
- Induction of plasminogen activator activity by phorbol ester in transformed fetal bovine aortic endothelial cells. Possible independence from protein kinase CBiochemical and Biophysical Research Communications, 1989
- Metabolism of receptor-bound and matrix-bound basic fibroblast growth factor by bovine capillary endothelial cells.The Journal of cell biology, 1988
- Phorbol ester induces cultured endothelial cells to invade a fibrin matrix in the presence of fibrinolytic inhibitorsJournal of Cellular Physiology, 1987
- Clinical Application of Inhibitors of FibrinolysisDrugs, 1985
- THE ATTRACTIONS OF PROTEINS FOR SMALL MOLECULES AND IONSAnnals of the New York Academy of Sciences, 1949