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1 Department of Pharmacology and Lung Vascular Biology Center, University of Illinois, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: abmalik{at}uic.edu.
Caveolin-1, the principal integral membrane protein of caveolae, has been implicated in regulating the structural integrity of caveolae, vesicular trafficking, and signal transduction. Although the functions of caveolin-1 are beginning to be explored in caveolin-1-/- mice, these results are confounded by unknown compensatory mechanisms and the development of pulmonary hypertension, cardiomyopathy, and lung fibrosis. To address the role of caveolin-1 in regulating lung vascular permeability, in the present study we used small interfering RNA (siRNA) to knock-down caveolin-1 expression in mouse lung endothelia in vivo. Intravenous injection of siRNA against caveolin-1 mRNA incorporated in liposomes selectively reduced the expression of caveolin-1 by ~90% within 96 hr of injection compared to wild-type mice. We observed the concomitant disappearance of caveolae in lung vessel endothelia and dilated inter-endothelial junctions (IEJs) as well as increased lung vascular permeability to albumin via IEJs. The reduced caveolin-1 expression also resulted in increased plasma NO concentration. The NOS inhibitor, L-NAME, in part, blocked the increased vascular albumin permeability. These morphological and functional effects of caveolin-1 knock-down were reversible within 168 hr after siRNA injection corresponding to the restoration of caveolin-1 expression. Thus, our results demonstrate the essential requirement of caveolin-1 in mediating the formation of caveolae in endothelial cells in vivo and in negatively regulating IEJ permeability.
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