Atherosclerotic lesion development occurs at sites of the vessel that are subject to disturbed flow and under conditions of low shear stress. Tissue factor (TF), the primary initiating factor in blood coagulation, is abundant in atherosclerotic plaques, and its content seems to predict plaque thrombogenicity. TF expression is also higher in areas of the arterial tree where there is disturbed flow. Recent evidence now suggest that platelet-endothelial cell adhesion molecule 1 (PECAM-1) has a proatherogenic role in the lesser curvature of the arch where disturbed flow predominates. Low density lipoprotein receptor null and ApoE null mice develop atherosclerosis in the lesser curvature of the aortic arch but not the descending thoracic and abdominal aorta when PECAM-1 is present.
My lab investigates how EC sense and respond to mechanical and chemical signals. Our current thrust has now been to try to understand how these cues interact and synergize around cell sensors, such as PECAM-1, to regulate dynamic vascular cell signaling and cell phenotype that promote atherogenesis. We investigate the effects of different patterns of uniform and disturbed mechanical forces on human EC expression of TF, and assess the activation of the relevant signal pathways and their regulation by PECAM-1 as the mechanosensor. The ability to sense and transduce local hemodynamic forces is unique to EC, suggest that the underlying mechanisms represent important therapeutic targets.