Caveolae May Show Local Short Range Motility A Role in Transendothelial Transport

In the above-mentioned bleaching studies a special FRAP protocol was included in which the entire interior of the cells was bleached, leaving only a narrow, fluorescent rim of GFP-tagged caveolin at the cell periphery [31]. These FRAP experiments highlighted two important points:

• The total fluorescence intensity of the peripheral rim including caveolae at the plasma membrane decreased only very slowly, further supporting the notion that caveolae are not becoming efficiently internalized (see also Section 4.6).

• There was a lively activity of the fluorescent caveolae at the cell periphery, although they did not disappear from the periphery (see Ref. [31], Fig. 5, online movie).

Whether this reflects that caveolae (or groups of caveolae) actually pinch off and refuse with the plasma membrane without really moving away from the subplasma-lemmal zone (for example, because they are tethered by the actin cytoskeleton), or it reflects movements in the plasma membrane with its population of caveolae as such, was not clear. However, such continuous recycling of caveolae immediately beneath the plasma membrane was recently demonstrated [40].

A short-range motility and fission-fusion processes may be highly relevant in order to understand the function of caveolae in transendothelial transport, or transcytosis. In endothelial transcytosis [41] caveolae are thought to give rise to free vesicles at one (lumenal or ablumenal) pole and thereafter move to and fuse with the opposite pole, thereby being involved in the exchange of macromolecules be tween the blood and the connective tissue. Although it is widely accepted, a major problem with the concept of transendothelial transcytosis in its strict meaning is that truly free, caveolar vesicles have been difficult or impossible to demonstrate ultrastructurally, both in conventionally fixed and rapidly frozen tissue [42-44]. However, considering that the distance between the lumenal and ablumenal membranes in the flattened endothelial cell is often around 200 nm, a short-range motility of the 50-70 nm caveolae or chains of caveolae and their apparent ability to fuse and detach again might explain how caveolae could be involved in transendothelial transport by a "kiss-and-run" activity, even without ever pinching off to form free, endocytic vesicles [17]. Such a process would most likely have to be highly regulated. In fact, the caveolar membrane and the endothelial cell cytoplasm contain the required molecular machinery [28,45,46], and transendothelial transport of albumin has been shown to require interaction of the albumin-docking protein pg60 with caveolin and activation of Gi-coupled Src kinase signaling [47]. Unfortunately, recent studies on caveolin-1-deficient mice have not clarified the role of caveolae in transendothelial transport. Thus, although lacking caveolae, these mice do not show any marked reduction in the transport of albumin [48,49]. This is most likely because caveolae also plays a more indirect role in vascular permeability. Vasorelaxation and permeability is regulated by eNOS, which is interacting with, and negatively regulated by, caveolin associated with endothelial caveolae [50]. In caveolin knockout mice, the microvasculature has even been reported to be hyperpermeable because of "opened" intercellular spaces and tight junctions apparently caused by uncontrolled release of and signaling via nitric oxide [51]. This hyperpermeability blurs any possible reduction in the cav-eolae-mediated transendothelial transport in the knockout mice.

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