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Endothelial Cell Response

Cardiovascular disease is the number one killer in the world, accounting for 30% of all deaths (1). Atherosclerotic plaques causing thrombosis (atherothrombosis) is the underlying pathology of the vast majority of cardiovascular diseases. It is responsible for up to 80% of all deaths in diabetic patients (2).  Atherothrombosis is clinically manifested as coronary artery disease (heart attacks), stroke, transient ischaemic attack, and peripheral arterial disease. The atherosclerotic process starts early in life and in almost 1/3 of all people, will progress to a complicated atheroscleotic plaque that generates thrombosis and blockage of blood supply.  These plaques preferentially develop in regions of complex blood flow such as bifurcations and regions of curvature (3).  Although many risk factors have been identified, none can explain the focal nature of the disease.  It is widely accepted that local variations in the forces created by blood flow (hemodynamic forces) is an initiating factor in focal atherosclerosis and its progression (4, 5).  The cells that line the blood vessels (endothelial cells) sense these forces and are believed to become dysfunctional in response to disturbed blood flow.  

Our understanding of the pathogenic mechanisms of atherosclerosis has been accelerated by the study of mechanically stimulated endothelial cells in vitro. Our Lab has developed a technique to make three dimensional vascular cell culture models which allow us to expose ECs and blood components to more realistic hemodynamic force patterns (13-15). We have used these methods to investigate the impact of vessel stenosis on EC function and studied the interactions between inflammatory cells and the endothelium. We have also used the technique to better understand the pleiotropic effects of statin therapy under flow conditions.    We are currently useing our models to study how endothelial cells sense spatial WSSGs.  We are investigating the role of the apical membrane of the cells (glycocalyx) in sensing WSSGs.  The glycocalyx has been hypothesized to transmit wall shear stress through the plasma membrane to the cell cytoskeleton. We are also investigating how cardiovascular therapies, such as statin treatment, alter EC function.

1    Dick M, Jonak P, Leask RL. Statin therapy influences endothelial cell morphology and F-actin cytoskeleton structure when exposed to static and laminar shear stress conditions. Life Sci 2013;92:859-865.
2    Rossi J, Rouleau L, Emmott A, Tardif JC, Leask RL. Laminar shear stress prevents simvastatin-induced adhesion molecule expression in cytokine activated endothelial cells. Eur J Pharmacol 2010;649:268-276.
3    Rossi J, Jonak P, Rouleau L, Danielczak L, Tardif JC, Leask RL. Differential response of endothelial cells to simvastatin when conditioned with steady, non-reversing pulsatile or oscillating shear stress. Ann Biomed Eng 2011;39:402-413.
4    Rouleau L, Farcas M, Tardif JC, Mongrain R, Leask RL. Endothelial cell morphologic response to asymmetric stenosis hemodynamics: effects of spatial wall shear stress gradients. J Biomech Eng 2010;132:081013.
5    Rouleau L, Rossi J, Leask RL. The response of human aortic endothelial cells in a stenotic hemodynamic environment: effect of duration, magnitude, and spatial gradients in wall shear stress. J Biomech Eng 2010;132:071015.
6    Rossi J, Rouleau L, Tardif JC, Leask RL. Effect of simvastatin on Kruppel-like factor2, endothelial nitric oxide synthase and thrombomodulin expression in endothelial cells under shear stress. Life Sci 2010;87:92-99.
7    Rouleau L, Copland IB, Tardif JC, Mongrain R, Leask RL. Neutrophil adhesion on endothelial cells in a novel asymmetric stenosis model: effect of wall shear stress gradients. Ann Biomed Eng 2010;38:2791-2804.
8    Rouleau L, Rossi J, Leask RL. Concentration and time effects of dextran exposure on endothelial cell viability, attachment, and inflammatory marker expression in vitro. Ann Biomed Eng 2010;38:1451-1462.
9    Farcas MA, Rouleau L, Fraser R, Leask RL. The development of 3-D, in vitro, endothelial culture models for the study of coronary artery disease. Biomed Eng Online 2009;8:30.
10   Leask RL, Jain N, Butany J. Endothelium and valvular diseases of the heart. Microsc Res Tech 2003;60:129-137.
11   Butany JW, Verma S, Leask RL, Mohsen B, Asa SL. Genetic abnormalities of the endothelium. Microsc Res Tech 2003;60:30-37.