Rapamycin inhibits VEGF-induced microvascular hyperpermeability in vivo

Area of Science:

• Pharmacology
• Vascular Biology
• Immunology

Background:

• Microvascular hyperpermeability is a key factor in inflammatory diseases.
• Vascular endothelial growth factor (VEGF) and platelet-activating factor (PAF) are known inducers of microvascular permeability.
• Rapamycin, an mTOR inhibitor, has shown anti-inflammatory properties.

Purpose of the Study:

• To investigate the direct in vivo effect of rapamycin on induced microvascular hyperpermeability.
• To determine the dose-dependent effects of rapamycin on vascular permeability.

Main Methods:

• Male golden Syrian hamsters were treated with varying doses of rapamycin or vehicle.
• Microvascular permeability was induced using VEGF or PAF.
• Integrated optical intensity (IOI) was used to assess microvascular permeability.
• Arteriolar diameter was measured to evaluate effects on vasodilation/vasoconstriction.

Main Results:

• Rapamycin significantly reduced VEGF-induced hyperpermeability at doses of 0.1, 0.5, and 2 mg/kg.
• A high dose (10 mg/kg) of rapamycin paradoxically increased VEGF-induced hyperpermeability.
• Rapamycin (0.5 mg/kg) attenuated VEGF-induced vasodilation and PAF-induced hyperpermeability.

Conclusions:

• Rapamycin inhibits VEGF- and PAF-induced microvascular permeability at therapeutically relevant concentrations.
• The inhibitory effect is a direct action on the endothelial barrier and independent of arteriolar vasodilation.
• High-dose rapamycin may stimulate pathways that increase microvascular permeability.