Feedback Effects of Extracellular Matrix Composition on AMPK Signaling Pathway: Pathway to Novel Drug Therapeutics Targeting Atherosclerosis

Atheroma is initiated and progressed in the unhealthy and artheroprone region of the blood vessel. During the process, the collagenous subendothelium (in the command of signaling pathways) is converted to a fibrillar subendothelium. This process involves the deposition of fibronectin and fibrinogen which alters the release of NO and the compliance of the vessel wall.^[2]Appropriate ECM composition establishes the functioning of the endothelial signaling pathways in the vascular intima. In this work, we use immunocytochemical methods that employ the distinct variations in extracellular matrix to study the characteristic behavior of endothelial cells in atheroprotective and atherogenic stages as shown in Table 1. We hypothesize that owing to different ECM configuration, AMP modified protein kinase (AMPK) phosphorylation will vary with flow.

For each experiment, the sterilized flow circuit is maintained at 37°C, ventilated with 95% humidified air - 5% CO₂, and connected to the peristaltic pump. A parallel-plate flow channel is used to impose laminar flow at 12 dyne/cm² for time intervals on confluent monolayer of endothelial cells (ECs). The contribution of extracellular matrix for atheroprone, atherogenic, and atherosclerotic stages of the vasculature and their effects on AMPK signaling pathway is explored through these in-vitro experiments (Figure 1).Exploring the stress-related AMPK signaling pathway provides striking insights into the onset and progression of atherosclerosis. A possible feedback response between NO production and ECM is identified.