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Rapamycin Inhibits VEGF‐Induced Microvascular Hyperpermeability In Vivo
Author(s) -
KIM DAVID D.,
KLEINMAN DAVID M.,
KANETAKA TAKEHITO,
GERRITSEN MARY E.,
NIVAGGIOLI THIERRY,
WEBER DAVID,
DURÁN WALTER N.
Publication year - 2010
Publication title -
microcirculation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.793
H-Index - 83
eISSN - 1549-8719
pISSN - 1073-9688
DOI - 10.1111/j.1549-8719.2009.00012.x
Subject(s) - cheek pouch , vasodilation , vascular permeability , vasoconstriction , vascular endothelial growth factor , angiogenesis , in vivo , microcirculation , chemistry , pharmacology , medicine , endocrinology , vegf receptors , biology , hamster , microbiology and biotechnology
Microcirculation (2010) 17 , 1–9. doi: 10.1111/j.1549‐8719.2009.00012.x Abstract Objective: To test the hypothesis that rapamycin inhibits induced microvascular hyperpermeability directly in vivo . Methods: Male golden Syrian hamsters (80–120 g) were treated with either rapamycin (at 0.1, 0.5, 2, and 10 mg/kg i.p.) or vehicle at 24 hours and at 1 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 platelet‐activating 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 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 PAF‐induced hyperpermeability, but did not inhibit PAF‐induced vasoconstriction. Conclusions: At therapeutically relevant concentrations, rapamycin inhibits VEGF‐ and PAF‐induced microvascular permeability. This inhibition is (i) a direct effect on the endothelial barrier, and (ii) independent of arteriolar vasodilation. Rapamycin at 10 mg/kg stimulates effectors that increase microvascular permeability.