Atherosclerotic arterial regions (bottom) show more PAK activation (left) and fibronectin deposition (right) compared with healthy regions (top).

Rivers rarely run a smooth course. Blood vessels, just like rivers, have turns, tributaries and other obstacles that create eddies and other irregularities in the flow. In vessels, such areas of disturbed flow are more permeable and more prone to atherosclerotic plaques. Orr et al. (page 719) now reveal that a matrix protein that is abundant at such sites might be the trigger for this increased permeability.

Vessel permeability is increased by the activation of endothelial cell p21-activated kinase (PAK), which promotes the cytoskeletal contraction that opens pores between cells. The team now shows that PAK is activated by the onset of laminar flow and that this activation is enhanced in atherosclerosis-prone sites in arteries.

Flow alone was not enough to induce permeability, however. PAK was strongly activated in cells adhered to fibronectin, which is made during injury and remodeling and found in atherosclerosis-prone regions. In contrast, normal basement membrane, which contains mostly laminin and collagen, did not support flow-mediated permeability. In mice, PAK activation and vessel permeability were high in atherosclerosis-prone, fibronectin-abundant regions. Inhibiting PAK reduced permeability in atherosclerotic mice.

General, long-term PAK inhibition is not a feasible means of atherosclerosis prevention, as PAK function is important in many cell types. Indeed pan-PAK inhibition was recently shown to induce Alzheimer-like symptoms in mice. Inhibiting the fibronectin-dependent pathway to PAK activation, however, might provide a more specific target for treatment.