Rapamycin inhibits VEGF-induced microvascular hyperpermeability in vivo.
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.
Kim
David D
DD
Program in Vascular Biology, Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, Newark, NJ 07101-1709, USA.
Kleinman
David M
DM
Kanetaka
Takehito
T
Gerritsen
Mary E
ME
Nivaggioli
Thierry
T
Weber
David
D
Durán
Walter N
WN
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001783:Blood Flow Velocity / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D002610:Cheek; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D009061:Mouth Mucosa / Q000098:blood supply / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D010972:Platelet Activating Factor; D042461:Vascular Endothelial Growth Factor A; D020123:Sirolimus