Reduced expression of basic fibroblast growth factor and its receptor mRNAs and proteins in portal hypertensive esophageal mucosa: a mechanism responsible for muscularis mucosae thinning and variceal rupture.
BACKGROUND
Basic fibroblast growth factor (bFGF) enhances cell migration, proliferation, and tissue integrity. This especially pertinent to the smooth muscle cells in which it stimulates cell proliferation and promotes their growth. The aim of this study was to determine whether expression of bFGF and its receptors (FGFR-1 and -2) is altered in portal hypertensive esophageal mucosa, especially in the muscularis mucosal layer, which constitutes a physical barrier to variceal rupture.


METHODS
Portal hypertension (PHT) was produced by staged portal vein ligation. In 30 PHT rats and 30 sham-operated controls 2 weeks after operation, specimens of lower esophagus were obtained for (1) quantitative histologic assessment including thickness of epithelium and muscularis mucosae; (2) immunostaining with specific antibodies against bFGF and its receptors 1 and 2 (intensity of bFGF, FGFR-1 and FGFR-2 immunostaining in esophageal structures was measured with a video image system); and (3) expression of bFGF and FGFR-1 and -2 mRNAs was assessed with reverse transcription-polymerase chain reaction.


RESULTS
The esophageal muscularis mucosae and epithelium overlaying large submucosal veins in PHT rats significatly thinner than those in controls (muscularis mucosae, 28.3 +/- 1.4 versus 52.2 +/- 8.0 micrometer, respectively, p<0.05); epithelium, 39.0+/- 7.1 versus 49.3 +/- 1.9 micrometer, respectively, p<0.05). The immunostaining intensity of bFGF and FGFR-2 was significantly reduced in PHT rats (42.1 +/- 2.3 and 71.3 +/- 6.5 units, respectively) versus controls (49.5 +/- 5.6 and 78.6 +/- 5.7 units, respectively, p< 0.05). Expressions of bFGF and FGFR-2 mRNAs in PHT esophageal mucosa were significantly reduced versus controls by 30.8% and 30.3%, respectively (p < 0.01, p 0.05).


CONCLUSIONS
(1) Esophageal mucosa of PHT rats has thinner muscularis mucosae and reduced bFGF and FGFR-2 mRNAs and proteins. (2) Because bFGF stimulates smooth muscle cell proliferation and their growth, our findings can explain thinning of esophageal muscularis mucosae in PHT rats, thus indicating a possible mechanism for rupture of varices in the esophagus.
Tanoue
K
K
Department of Surgery, Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.
Tarnawski
A S
AS
Santos
A M
AM
Hanke
S
S
Sugimachi
K
K
Sarfeh
I J
IJ
D000818:Animals; D001483:Base Sequence; D004932:Esophageal and Gastric Varices / Q000150:complications*; D004947:Esophagus / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000032:analysis / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006975:Hypertension, Portal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000235:genetics*
D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2