Rapamycin prevents mesenteric neo-angiogenesis and reduces splanchnic blood flow in portal hypertensive mice.
OBJECTIVE
Increased angiogenesis in the mesenteric microvasculature of portal hypertensive animals may contribute to the development of splanchnic vasodilation associated with portal hypertension (PHT). Experimental data suggest that rapamycin may reduce angiogenesis and tumour growth by inhibiting the vascular endothelial growth factor (VEGF) pathway. This study determines whether rapamycin can prevent the neoangiogenesis in the mesentery of portal hypertensive mice and may influence the splanchnic vasodilation.


METHODS
PHT was induced by partial portal vein ligation (PPVL). PPVL and Sham mice were treated daily with rapamycin or placebo for 2 weeks. Protein expressions of VEGF, CD 31, Akt and p70S6 kinase (mTOR signalling pathway) were evaluated. Mesenteric blood flow (MBF) was measured by a perivascular flow probe.


RESULTS
Increased mesenteric angiogenesis and VEGF protein levels were observed in PPVL(placebo) mice compared to Sham(placebo) mice. Rapamycin treatment caused significant reduction in CD 31 positive endothelial cells and VEGF protein in the PPVL(rapamycine) group compared to the PPVL(placebo) group, to levels comparable with Sham(placebo) and Sham(rapamycine) groups. MBF was significantly higher in PPVL(placebo) mice compared to the Sham(placebo) mice. Rapamycin decreased significantly the MBF in PPVL(rapamycine) mice compared to PPVL(placebo) mice. Phospo-Akt and p70S6 kinase protein levels were increased in the mesenteric tissue of PPVL(placebo) mice compared to Sham(placebo) mice, which were also prevented by treatment with rapamycin.


CONCLUSIONS
An increased VEGF dependent neo-angiogenesis is present in the mesentery of portal hypertensive mice. Rapamycin prevents angiogenesis in the mesenteric tissue and decreases the mesenteric blood flow in portal hypertensive mice, at least in part through an anti-VEGF activity and influence on the mTOR signalling pathway.
Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Anja M
AM
Geerts
Eline
E
Vanheule
Hans
H
Van Vlierberghe
Luc
L
Leybaert
Christophe
C
Van Steenkiste
Martine
M
De Vos
Isabelle
I
Colle