Localisation and differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal and atherosclerotic human arteries.
OBJECTIVE
Aberrant expression of FGF-1 and FGF-2 may be central to the atherosclerotic disease process, promoting both intimal hyperplasia and plaque neovascularisation. FGF-1 and FGF-2 mediate their biological effects by binding to a family of specific high-affinity cell surface receptors with protein tyrosine kinase activity. Four receptors have been identified in the human (FGFR1/flg gene product, FGFR2/bek gene product, FGFR3 and FGFR4), but little is known of their in vivo tissue distribution. Characterisation of the spatial distribution of the FGFR multigene family in both normal and atherosclerotic arteries is a prerequisite to further define the functional role of FGF-1 and FGF-2 in atherosclerosis. The objective of this study was to examine the cell-type-specific expression of the FGFR multigene family members in both normal and atherosclerotic human arteries.


METHODS
FGFR expression was investigated immunocytochemically with polyclonal antisera to FGFR1-4 and by in situ hybridisation using FGFR1-4 riboprobes in archival material. Total cellular mRNA was analysed using poly d(T) and the levels correlated with the expression of FGFR1-4 mRNA.


RESULTS
At the protein level, FGFR1-4 were expressed in the medial smooth muscle cells and adventitial vessels of normal arteries. In simple and advanced lesions, the expression profiles of FGFR1-4 showed variability between individual arteries, and cell-type-specific differential FGFR expression was apparent. Widespread co-expression of FGFR1 and FGFR2 was observed in intimal smooth muscle cells, foam cells and the plaque microvasculature of simple and advanced lesions. FGFR3 and FGFR4 exhibited more restricted patterns of distribution within the plaque. In situ hybridisation with poly d(T) confirmed high cellular transcriptional activity in archival atherosclerotic lesions. The high levels of total cellular mRNA and FGFR protein were not always reciprocated at the FGFR1-4 mRNA level, and only FGFR1 and FGFR2 mRNA transcripts were abundant in intimal lesions.


CONCLUSIONS
These data provide evidence to suggest involvement of the FGF-FGFR multigene families in human atherogenesis. Differential FGFR expression in plaque subtypes may reflect distinct differences in receptor function which may be relevant to lesion progression during atherosclerosis.
Hughes
S E
SE
Division of Histopathology, United Medical and Dental Schools (UMDS), London, UK.
D000328:Adult; D000368:Aged; D001158:Arteries / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors; D000091344:Filaggrin Proteins; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis* / Q000235:genetics
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; C496371:FGFR4 protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4