Beyond impressions how altered shear stress connects hypoxic signaling to endothelial inflammation

Atherosclerotic lesions form preferentially in arterial regions characterized by slow and irregular patterns of blood flow such as those found on the inner curvature of bifurcation branch points. Because of this nonrandom distribution, extensive research has focused on the role of shear stress or the mechanical drag force exerted on the endothelial lining of blood vessels. Blood flow that follows a high shear stress, unimpeded laminar pattern encourages homeostatic mechanisms in the endothelium and protects against atherosclerosis. The transition from laminar to disturbed flow elicits changes in endothelial cell behavior that include increased inflammatory signaling through the activation of NF-κB, increased expression of leukocyte adhesion receptors, and the recruitment of immune cells. Focal areas exposed to detrimental shear stress, together with the synergistic effects of dyslipidemia, age, and hyperglycemia, initiate and promote the growth of atherosclerotic lesions. The mechanisms by which endothelial cells sense and respond to these changes in flow have been intensively studied, but gaps in our knowledge remain. See accompanying article on page 2087 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Feng et al1 report on the ability of low shear stress to upregulate HIF-1α and glycolytic programming in endothelial cells. HIF-1α is a master regulator of the cellular response to hypoxia, and its expression is associated with changes in metabolism, inflammation, and angiogenesis.2,3 The ability of low oxygen tensions to increase atherosclerosis in ApoE-null mice4 and the genetic deletion of HIF-1α, selectively in endothelial cells5 or in macrophages,6 to protect against atherosclerosis collectively suggest that hypoxia plays a pathogenic role. Arterial blood carries abundant levels of oxygen, and, therefore, hypoxia has been hypothesized to occur deep within the core of large atherosclerotic lesions, and this is supported by the detection of low oxygen concentrations and HIF-1α …