The type of fluid flow and mechanical shear stress in the vasculature regulate many processes of vascular homeostasis, such as vascular remodelling, cardiac development and atherogenesis. Whereas atherosclerotic lesions tend not to be found in blood vessels where there are regions of high laminar shear flow, the opposite is true in regions of low shear stress or in disturbed areas, such as vessel branch points. The endothelial cells that line these vessels somehow sense the different patterns of mechanical stress on the vessel walls. In a recent issue of Nature, Schwartz and colleagues identify a mechanosensory complex that mediates the endothelial response to fluid shear stress. This work suggests the possibility of therapeutic intervention at an early stage of the atherosclerotic process.

The onset of shear stress triggers a number of events in endothelial cells, including the activation of cell surface receptors, kinases and transcription factors such as nuclear factor-B (NF-B) and the phosphorylation of platelet endothelial cell-adhesion molecule-1 (PECAM1). In laminar flow, vascular endothelial cells adapt to the flow, so that after the initial stimulation these events are down regulated. By contrast, in disturbed-flow conditions these pathways are activated in a sustained manner, resulting in expression of a variety of molecules, such as the integrins intercellular cell-adhesion molecule-1 (ICAM1), vascular cell-adhesion molecule-1 (VCAM-1), E-selectin and platelet-derived growth factor (PDGF), which when activated are known to activate NF-B. These markers are expressed at atherosclerosis-prone sites before other markers for atherosclerosis.

Tzima et al. show that three proteins — PECAM-1, vascular endothelial (VE) cell cadherin and VE growth factor receptor-2 (VEGFR2), which are expressed in vessel endothelial cells — are required for detecting mechanical stress. Each protein has a distinct role in converting the mechanical force into a biochemical signal inside the cells: PECAM1 directly transmits mechanical force; VE cell cadherin functions as an adaptor; and VEGFR2 activates the downstream kinase phosphatidylinositol-3-OH kinase (PI3K). PI3K has been implicated in integrin activation in many cell types. To demonstrate the importance of this pathway in vivo the authors show that PECAM1-deficient mice do not activate NF-B and downstream inflammatory genes in regions of disturbed flow.

These new findings shed light on the earliest known events in atherogenesis, explaining the mechanics of how disruptions in blood flow stimulate endothelial cells and trigger the formation of atherosclerotic plaques. Opportunities for intervention are not instantly obvious. PECAM1 would not be a good target to block as it is beneficial in regions of arteries in which flow is laminar, where among other things it contributes to the production of nitric oxide and vasodilation. However, blocking the integrin pathway might provide a strategy for blocking the inflammatory effects of flow.

Author: Melanie Brazil - Copyright © 2005 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission