Expression pattern of fibroblast growth factors (FGFs), their receptors and antagonists in primary endothelial cells and vascular smooth muscle cells

Abstract

Fibroblast growth factors (FGFs) are important angiogenic growth factors. While basic FGF (FGF2) is well established as a potent inducer of angiogenesis much less is known about other FGFs possibly expressed by EC. We investigated the expression of all known FGFs, their main tyrosine kinase receptors and antagonists by RT-PCR analysis in human umbilical vascular endothelial cells (HUVECs) to obtain a complete expression profile of this important growth factor system in model endothelial cells (EC). In addition to FGFR1IIIc, which is considered as the major FGF receptor in EC, HUVECs express similar levels of FGFR3IIIc, detectable amounts of FGFR2IIIc and a new FGF receptor without an intracellular kinase domain (FGFR5). HUVECs express several secreted FGFs, including FGF5, 7, 8, 16 and 18 and two members of the fibroblast growth factor homologous factors (FHFs), not yet reported to be expressed in EC. The expression panel was compared with that obtained from human vascular smooth muscle cells (VSMCs) and human aortic tissue. Human umbilical artery smooth muscle cells (HUASMCs) and HUVECs express the identical FGF receptor and ligand panel implicating that both cell types act, according the FGF signals more as an entity than as individual cell types. Expression of Fgf1, 2, 7, 16 and 18 and the antagonists Sprouty 2,3 and 4 was demonstrated for all analysed cDNAs. The IIIc isoforms of FGFR1 and 2 and the novel FGFR5 were expressed in the aorta, but expression of the FGF receptor 3 was not detected in cDNAs derived from aortic tissue. In the VSMC of rat aortic tissue and in HUASM cultured cells we could demonstrate FGF18 immunoreactivity in the nucleus of the cells. The expression of several secreted FGFs by EC may focus the view more on their paracrine effects on neighbouring cells during tissue regeneration or tumor formation.

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Even though a comprehensive study is still missing, endothelial cells express different members of the FGFR family, FGFR1IIIc being the most represented receptor while FGFR2-IIIc and FGFR3-IIIc are expressed at lower levels [40]. Experiments performed on FGFR1 and FGFR2 null mice in both endothelial and hematopoietic cells indicate that these receptors are not required for vascular homeostasis or physiological functions.…”

“…Of note, human umbilical vascular endothelial (HUVE) cells express several canonical FGFs (including FGF1, FGF2, FGF5, FGF7, FGF8, FGF16, FGF18) and two FGF homologous factors (FGF11 and FGF12) [40], thus suggesting that FGFs may also exert autocrine functions in endothelium.…”

Fibroblast growth factor 18 promotes proliferation and migration of H460 cells via the ERK and p38 signaling pathways

“…FGF family members are involved in cell growth, differentiation, morphogenesis, tissue repair, inflammation, angiogenesis, tumor growth and numerous developmental processes including embryonic and skeletal development (5)(6)(7)(8)(9). As such, the role of the FGF family has been widely studied during tumor growth and metastasis and has been shown to increase the proliferation, motility and invasiveness of a range of cell types (10,11).…”

DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling

“…Among them, FGF-2 is known to stimulate angiogenesis in vivo 2 and promote endothelial cell proliferation, chemotaxis and tube formation in vitro 1,3 . In endothelial cells, FGF-2 exerts its biological effects mainly by activating fibroblast growth factor receptor-1 (FGFR-1) [4][5][6][7] , which is a member of the tyrosine kinase receptor family [8][9][10] . FGF-2 also induces VEGF expression in endothelial cells through autocrine and paracrine mechanisms 11 .…”