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1 Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA
2 Department of Pathology and Physiology Branch, NIOSH HELD, Morgantown, WV, USA
* To whom correspondence should be addressed. E-mail: phe{at}hsc.wvu.edu.
We demonstrated previously that the inhibition of endothelial nitric oxide synthase (NOS), using pharmacological inhibitors, attenuated the ionomycin- and ATP-induced increases in microvessel permeability (He et al., Am J Physiol 272: H176-185, 1997). Recently, the scaffolding domain of caveolin-1 (CAV) has been implicated as a negative regulator of eNOS in endothelial cells. To examine the role of CAV-eNOS interaction in the regulation of permeability in intact microvessels, the effect of internalized CAV on PAF-induced permeability increase was investigated in rat mesenteric venular microvessels. The internalization of CAV was achieved by perfusing individual vessels using a fusion peptide of CAV with Antennapedia homeodomain (AP-CAV) and visualized with fluorescence imaging and electron microscopy. Changes in microvessel permeability were evaluated by measuring hydraulic conductivity (Lp) in individually perfused microvessels. Results demonstrated that a 2h perfusion with AP-CAV (10 µ]M) significantly attenuated PAF (10 nM)-induced Lp increase from 6.0 ± 0.9 (n=7) to 2.0 ± 0.3 (n=5) times the control value. The magnitude of this reduction is comparable with that of the inhibitory effect of L-NMMA on PAF-induced Lp increase. In contrast, perfusion with AP (10 µM) alone for 2h modified neither basal Lp nor the vessel response to PAF. These results indicated that CAV plays an important role in the regulation of microvessel permeability. Its inhibitory action on the permeability increase might be attributed to its direct inactivation of eNOS. In addition, this study supports that AP is an efficient tool for translocating peptide across the cell membrane to study protein-protein interaction-induced functional changes in vivo.
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