Basic Fibroblast Growth Factor–Induced Angiogenic Phenotype in Mouse Endothelium

Author:

Bastaki Maria1,Nelli Enrico Emanuele1,Dell’Era Patrizia1,Rusnati Marco1,Molinari-Tosatti Maria Pia1,Parolini Silvia1,Auerbach Robert1,Ruco Luigi P.1,Possati Laura1,Presta Marco1

Affiliation:

1. 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,...

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

Reference60 articles.

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