Vasodilation Endothelial Permeability and CaveolineNOS Interaction

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The role of caveolae in endothelium-dependent and NO-mediated vascular relaxation was documented in the original papers reporting the phenotype of caveolin-deficient mice by the groups of Kurzchalia and Lisanti [48,49]. These authors have, indeed, evaluated the NO-mediated vasorelaxing effects of acetylcholine on aortic rings precontracted with phenylephrine (an a1-adrenergic vasoconstrictor). Both groups reported a significantly greater relaxation in Cav-1 null aortic rings at all acetylcholine concentrations examined. Drab et al. further documented that, in primary culture of aortic vascular smooth muscle cells, the basal release of NO was one-third higher than in wild-type cells and the content of cyclic guanosine monophosphate (cGMP) was about three-fold higher in knockout animals [48]. Raz-zani et al. also found that, in the presence of the NOS inhibitor L-NAME, the increase in contractile response to phenylephrine was significantly greater in the Cav-1 null mice [49].

That eNOS becomes hyperactivated in the absence of caveolin-1 formed the basis for further studies exploring this paradigm in a variety of biological contexts, including agonist- and shear stress-induced vasoresponse as well as disease states. For example, Omura et al. reported that eicosapentaenoic acid stimulated NO production and the associated endothelium-dependent relaxation through stimulation of the dissociation of the caveolin-eNOS complex [50]. Similarly, increasing vascular flow (which is by far the main in-vivo trigger for vasodilation) was shown rapidly to activate caveolar eNOS by inducing calmodulin-dependent eNOS dissociation from caveolin [51]. By contrast, in a model of portal hypertension, Shah et al. [52] found that caveolin expression was significantly increased in liver sinusoids and venules, thereby leading to a significant reduction in NO production. An abnormal tight coupling between eNOS and caveolin was also identified by Murata et al. in a rat model of hypoxia-induced pulmonary hypertension (another disease state which is in part due to impaired bioactivity of vascular NO) [53]. These authors documented that, in the hypoxic pulmonary artery, the increased caveolin-eNOS interaction accounted for the impaired eNOS activity in either the presence or absence of carbachol. In yet another study, Pelligrino et al. attributed the defect in acetylcholine-induced vasodilation of ovariectomized rat pial arteries to caveolin. More exactly, they found that the endothelial dysfunction observed in these operated rats could be reversed by estradiol treatment through a reduction in endothe-lial caveolin-1 expression [54]. Finally, using isolated tumor arterioles mounted on a pressure myograph, we documented that local tumor irradiation induced NO-mediated vasorelaxation through not only an increase in the abundance of eNOS but also a decrease in caveolin-1 expression [55].

Besides vasodilation, caveolin-eNOS interaction has also been proposed to impact on vascular permeability. Caldwell et al. initially reported that VEGF increased endothelial cell permeability by an eNOS-dependent mechanism of transcytosis in caveolae and also, interestingly, that VEGF-R2 and eNOS co-localized with caveolin-1 in plasma membrane caveolae in retinal microvascular endothelial cells [56]. The same authors then documented that VEGF stimulated the translocation of eNOS, caveolin-1 and the VEGF receptor into the nucleus [57]. In the context of inflammation and tumor angiogenesis, Sessa's group also identified a role for caveolin in endothelial cell permeability. Accordingly, Bucci et al. used two experimental inflammatory models (subplantar administration of carrageenan and ear application of mustard oil) to examine the effects of the CSD on induced permeability [58]. These authors showed that the systemic administration of CSD-derived peptides fused with a cellular internalization sequence (derived from the Antennapedia homeodomain) suppressed acute inflammation and vascular leak to the same extent as the NOS inhibitor L-NAME. Gratton et al. showed that the same fusion peptide inhibited eNOS-dependent vascular leakage in tumors and consecutively delayed tumor progression in mice [59]; extravasation of plasma proteins is, indeed, known to contribute to the formation of a provisional matrix required to initiate neoangiogenesis.

Taken together, these data emphasize the key role of caveolin and caveolae in regulating smooth muscle relaxation and endothelial permeability. The results of several studies have also suggested that activated eNOS, as observed in inflammation, tumors or hypoxia (versus healthy tissues), is particularly sensitive to alterations in the caveolin pool, thereby opening new perspectives of treatments (using, for example, CSD-derived peptides).

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