Flow-dependent cellular mechanotransduction in atherosclerosis

Abstract

Atherosclerosis depends on risk factors such as hyperlipidemia, smoking, hypertension and diabetes. Although these risk factors are relatively constant throughout the arterial circulation, atherosclerotic plaques occur at specific sites where flow patterns are disturbed, with lower overall magnitude and complex changes in speed and direction. Research over the past few decades has provided new insights into the cellular mechanisms of force transduction and how mechanical effects act in concert with conventional risk factors to mediate plaque formation and progression. This Commentary summarizes our current understanding of how mechanotransduction pathways synergize with conventional risk factors in atherosclerosis. We attempt to integrate cellular studies with animal and clinical data, and highlight major questions that need to be answered to develop more effective therapies.

Keywords: Endothelium; Fluid shear stress; Vascular biology.

Fig. 1.

Illustration of disturbed arterial flow. Schematic illustration of calculated flow patterns (as shown in the graph) in an idealized model of the human aorta. Q inlet refers to flow rate at the entrance to the aorta. The black dot in the graph denotes the specific time during the cardiac cycle to which the streamlines and wall shear stress (WSS) images correspond. Stream lines in the enlargements show velocity color coded according to the key. The enlargement at the top shows the region of disturbed flow at the inner curvature of the aortic arch. The enlarged region at the bottom illustrates disturbed flow at branches off the abdominal aorta. WSS just after the start of diastole is illustrated on the right. Courtesy of Alberto Figueroa and Nan Xiao, King's College London, UK.

Fig. 2.

Initiation of atherosclerosis by disturbed flow. (A) Inflammatory signaling. Fluid shear stress activates the PECAM–VE-cadherin–VEGFR2 pathway, which activates integrin signaling. Fluid shear also increases the expression of fibronectin and induces the assembly of the fibronectin matrix. Fibronectin switches integrin signaling to pro-inflammatory pathways, resulting in activation of NF-κB, PAK and JNK among others. (B) Anti-inflammatory signaling. Fibronectin also suppresses the flow activation of eNOS and production of nitric oxide (NO), thus inhibiting a major anti-inflammatory pathway. As a result, endothelial cells increase their expression of the leukocyte recruitment receptors ICAM-1 and VCAM-1, and a variety of cytokines. The combination of these effects results in the recruitment of monocytes and other leukocytes to the vessel wall. NO also decreases smooth muscle cell (SMC) contraction to reduce blood pressure (BP), and inhibits platelet reactivity, which also suppresses atherogenesis.

Fig. 3.

Interaction of disturbed flow with conventional risk factors. Endothelial activation and leukocyte recruitment to regions of disturbed flow synergize with other factors that promote atherosclerosis. High glucose levels in diabetes patients upregulate fibronectin expression, thus promoting NF-κB and inhibiting NO production. Increased endothelial permeability and ECM remodeling promote the entry and retention of low density lipids (LDLs) in the vessel wall. In addition, diabetes, smoking, hypertension and hyperlipidemia all increase reactive oxygen species (ROS). These provide a further inflammatory stimulus; they promote oxidization of LDLs (oxLDL) and react with NO to decrease its availability. Monocyte or macrophages that are recruited through the pathway illustrated in Fig. 2 ingest oxLDL and are activated to foam cells.