Rapamycin Inhibits VEGF-Induced Microvascular Hyperpermeability In Vivo

• Published in: Microcirculation (New York, N.Y. 1994) Vol. 17; no. 2; pp. 128 - 136
• Main Authors: KIM, DAVID D., KLEINMAN, DAVID M., KANETAKA, TAKEHITO, GERRITSEN, MARY E., NIVAGGIOLI, THIERRY, WEBER, DAVID, DURÁN, WALTER N.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2010
• Subjects: Animals; arteriolar diameter; Arterioles - drug effects; Arterioles - physiology; Blood Flow Velocity - drug effects; Capillary Permeability - drug effects; Cheek; Cricetinae; Male; Mesocricetus; Microcirculation - drug effects; Microcirculation - physiology; microvascular permeability; Mouth Mucosa - blood supply; Mouth Mucosa - drug effects; mTOR; PAF; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - pharmacology; rapamycin; Sirolimus - pharmacology; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - pharmacology; Vasodilation - drug effects; VEGF
• ISSN: 1073-9688; 1549-8719
• DOI: 10.1111/j.1549-8719.2009.00012.x

Microcirculation (2010) 17, 1–9. doi: 10.1111/j.1549‐8719.2009.00012.x 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.