AimsIn this study, we investigated the mechanisms by which caveolin-1 (CAV) inhibits increases in permeability induced by platelet activating factor (PAF) and elucidated the relationship between the endothelial intracellular Ca 2+ concentration ([Ca2+]i) and CAV in regulating endothelial nitric oxide synthase (eNOS) activity and microvessel permeability in intact microvessels.Methods and resultsExperiments were conducted in individually perfused mesenteric venules in Sprague-Dawley rats. Permeability was determined by measuring hydraulic conductivity (Lp). Endothelial [Ca 2+]i and nitric oxide (NO) production were measured in fura-2-and DAF-2-loaded microvessels. Perfusion of the CAV scaffolding domain, AP-CAV, at 1 M for 30 min did not affect PAF-induced increases in endothelial [Ca 2+]i but significantly attenuated PAF-induced NO production from 143 ± 2 to 110 ± 3 of control fluorescence intensity (FI). The PAF-induced Lp increase was correlatively reduced from a mean peak value of 7.5 ± 0.9 to 1.9 ± 0.5 times that of the control. Increasing extracellular [Ca2+] that potentiated PAF-induced peak [Ca 2+]i from 500 to 1225 nM augmented NO production to 193 ± 13 and further increased Lp to 17.3 ± 1.6 times the control value. More importantly, enhanced Ca2+ influx restored the reduced NO production and Lp by AP-CAV with NO FI at 149 and Lp at 7.7 ± 1.1 times the control value.ConclusionOur results indicate that eNOS inhibition and reduced NO production contribute to the inhibitory action of AP-CAV on PAF-induced increases in permeability. CAV and endothelial [Ca2+]i antagonistically regulate eNOS activity in intact microvessels, and the level of produced NO is the key determinant of the degree of permeability increases during inflammation.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- Physiology (medical)