Rapamycin prevents mesenteric neo-angiogenesis and reduces splanchnic blood flow in portal hypertensive mice

• Published in: Hepatology research 2008-11, Vol.38 (11), p.1130-1139
• Main Authors: Geerts, Anja M., Vanheule, Eline, Van Vlierberghe, Hans, Leybaert, Luc, Van Steenkiste, Christophe, De Vos, Martine, Colle, Isabelle
• Format: Article
• Language: English
• Subjects: angiogenesis; hyperdynamic circulation; portal hypertension; sirolimus
• ISSN: 1386-6346; 1872-034X
• DOI: 10.1111/j.1872-034X.2008.00369.x

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 PPVLplacebo mice compared to Shamplacebo mice. Rapamycin treatment caused significant reduction in CD 31 positive endothelial cells and VEGF protein in the PPVLrapamycine group compared to the PPVLplacebo group, to levels comparable with Shamplacebo and Shamrapamycine groups. MBF was significantly higher in PPVLplacebo mice compared to the Shamplacebo mice. Rapamycin decreased significantly the MBF in PPVLrapamycine mice compared to PPVLplacebo mice. Phospo‐Akt and p70S6 kinase protein levels were increased in the mesenteric tissue of PPVLplacebo mice compared to Shamplacebo 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.