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Internalization of caveolin-1 scaffolding domain facilitated by Antennapedia homeodomain attenuates PAF-induced increase in microvessel permeability

¹Department of Physiology and Pharmacology, West Virginia University, and ²Pathology and Physiology Branch, Health Effects Laboratory Division, National Institute of Occupational Safety and Health, Morgantown, West Virginia 26506

Submitted 14 July 2003 ; accepted in final form 25 August 2003

We demonstrated previously that inhibition of endothelial nitric oxide synthase (NOS), using pharmacological inhibitors, attenuated the ionomycin- and ATP-induced increases in microvessel permeability (Am J Physiol Heart Circ Physiol 272: H176–H185, 1997). Recently, the scaffolding domain of caveolin-1 (CAV) has been implicated as a negative regulator of endothelial NOS (eNOS). To examine the role of CAV-eNOS interaction in regulation of permeability in intact microvessels, the effect of internalized CAV on the platelet-activating factor (PAF)-induced permeability increase was investigated in rat mesenteric venular microvessels. Internalization of CAV was achieved by perfusion of individual vessels using a fusion peptide of CAV with Antennapedia homeodomain (AP-CAV) and visualized by fluorescence imaging and electron microscopy. Changes in microvessel permeability were evaluated by measuring hydraulic conductivity (L_p) in individually perfused microvessels. We found that the PAF (10 nM)-induced L_p increase was significantly attenuated from 6.0 ± 0.9 (n = 7) to 2.0 ± 0.3 (n = 5) times control after microvessels were perfused with 10 µM AP-CAV for 2 h. The magnitude of this reduction is comparable with that of the inhibitory effect of N-monomethyl-L-arginine on the PAF-induced L_p increase. In contrast, perfusion with 10 µM AP alone for 2 h modified neither basal L_p nor the vessel response to PAF. These results indicate that CAV plays an important role in regulation of microvessel permeability. The inhibitory action of CAV on permeability increase might be attributed to its direct inactivation of eNOS. In addition, this study established a method for studying protein-protein interaction-induced functional changes in intact microvessels and demonstrated AP as an efficient vector for translocation of peptide across the cell membrane in vivo.

endothelial nitric oxide synthase; nitric oxide; caveolae; individually perfused venular microvessel; hydraulic conductivity

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