Rapamycin Inhibits VEGF-Induced Microvascular HyperpermeabilityIn Vivo

DAVID D. KIM, DAVID M. KLEINMAN, TAKEHITO KANETAKA, MARY E. GERRITSEN, THIERRY NIVAGGIOLI, DAVID WEBER, WALTER N. DURÁN
2010 Microcirculation  
Objective-To test the hypothesis that rapamycin inhibits induced microvascular hyperpermeability directly in vivo. Methods-Male golden Syrian hamsters (80-120g) were treated with either rapamycin (at 0.1, 0.5, 2, and 10 mg/kg i.p.) or vehicle at 24 hours and at one hour prior to preparation of the cheek pouch. Caveolin-1 scaffolding (1 mg/kg; positive inhibitory control) was injected i.p. 24 hours prior to the experiment. 10 −8 M vascular endothelial growth factor (VEGF) or 10 −7 M
more » ... ating factor (PAF) were topically applied to the cheek pouch. Microvascular permeability and arteriolar diameter were assessed using integrated optical intensity (IOI) and vascular wall imaging, respectively. Results-Rapamycin at 0.1 mg/kg and 0.5 mg/kg significantly reduced VEGF-stimulated mean IOI from 63.0±4.2 to 9.7±5.0 (85% reduction, P<0.001) and 3.6±2.7 (95% reduction, P<0.001), respectively. Rapamycin at 2 mg/kg also lowered VEGF-stimulated hyperpermeability (40% reduction, P<0.05). However, 10 mg/kg rapamycin increased VEGF-induced microvascular hyperpermeability. Rapamycin at 0.5 mg/kg attenuated VEGF-induced vasodilation and PAFinduced hyperpermeability, but did not inhibit PAF-induced vasoconstriction. Conclusions-At therapeutically relevant concentrations, rapamycin inhibits VEGF-and PAFinduced microvascular permeability. This inhibition is 1) a direct effect on the endothelial barrier, and 2) independent of arteriolar vasodilation. Rapamycin at 10 mg/kg stimulates effectors that increase microvascular permeability.
doi:10.1111/j.1549-8719.2009.00012.x pmid:20163539 pmcid:PMC2925471 fatcat:gazbxmm2g5cl3lbvbjuwndukyq