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Rapamycin prevents mesenteric neo‐angiogenesis and reduces splanchnic blood flow in portal hypertensive mice
Author(s) -
Geerts Anja M.,
Vanheule Eline,
Van Vlierberghe Hans,
Leybaert Luc,
Van Steenkiste Christophe,
De Vos Martine,
Colle Isabelle
Publication year - 2008
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2008.00369.x
Subject(s) - splanchnic , angiogenesis , medicine , endocrinology , vasodilation , vascular endothelial growth factor , portal hypertension , pi3k/akt/mtor pathway , placebo , portal venous pressure , mesenteric arteries , hemodynamics , pathology , biology , signal transduction , vegf receptors , artery , biochemistry , cirrhosis , alternative medicine
Aim: 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.