Proteins and other substances can cross the endothelial layer that lines a blood vessel via two routes. Caveolin-1 is essential for both, Siddiqui et al. show.

Researchers already knew that caveolin-1 was necessary for transcellular protein trafficking, in which macromolecules such as albumin enter an endothelial cell from the bloodstream and exit on the tissue side. Caveolae swallow these molecular travelers and bundle them into vesicles that wend through the cell. In an alternative pathway, known as the paracellular route, molecules slip between the cells of the endothelial layer, passing through the adherens junctions that fasten adjacent cells together. Previous work showed that adherens junctions become permeable in mice lacking caveolin-1, suggesting that the protein helps seal the junctions.

Siddiqui et al. dissected the molecular chain of events that connects caveolin-1 to adherens junction integrity. Loss of caveolin-1 activated the enzyme eNOS, which spawns nitric oxide (NO) that reacts to form peroxynitrite. In turn, peroxynitrite modifies the adherens junction protein p190RhoGAP-A, preventing it from inhibiting RhoA. Activated RhoA then tweaks the cytoskeleton at adherens junctions, making them leaky. The researchers found that they could reseal the junctions by blocking eNOS or RhoA activity.

The inflammation-promoting enzyme thrombin also tampers with adherens junctions through this pathway, Siddiqui et al. found. An open question, they say, is whether such disruption allows fluid buildup and migration of inflammatory cells across the endothelial layer, both of which are characteristic of inflammation.

et al
J. Cell Biol.