Atherosclerosis: Cardiovascular Dynamics and Biomolecular Transport

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The Wallace Coulter Laboratory for Cardiovascular Dynamics and Biomolecular Transport at the City College of New York studies the role of fluid dynamical mechanisms and transport processes in the physiological and pathophysiological functions of the cardiovascular system. A major effort is to understand the influence of fluid dynamics in the initiation and progression of atherosclerosis. These researchers are investigating the fluid mechanics of arteries and the response of arterial cells (endothelial and smooth muscle cells) to fluid mechanical forces using cell culture models in vitro and computer simulations. They were the first to compute the fluid flow shear stresses on smooth muscle cells (SMC’s) induced by transmural flow and have subsequently exposed cultures of SMC’s to similar stress environments in defined flow fields to determine their biomolecular responses.

The Lab is uniquely positioned to investigate new approaches to pathological hemodynamics and their possible manipulation by pharmaceuticals. While wall shear stress (WSS) has been the traditional focus of cardiovascular pathology research, these researchers have simulated WSS along with an often neglected hemodynamic feature, circumferential strain (CS), to demonstrate that the asynchrony between WSS and CS has an important effect on EC biochemical response. The results suggest that naturally asynchronous hemodyamics of the coronary arteries may predispose them to over express atherogenic genes and under express anti-atherogenic genes. Subsequent research indicates that certain neutraceuticals may be useful in normalizing the atherogenic gene expression pattern induced by the natural hemodynamic environment of the coronaries.

In complementary research these Coulter Lab researchers have pioneered in vitro studies of convection and diffusion of macromolecules across monolayers of endothelial cells which form the blood contacting surface of all blood vessels. They have clearly demonstrated that the transport properties of endothelial layer are very sensitive to their fluid mechanical environment and will respond to changes in fluid shear stress. Studies of biomolecular mechanisms underlying these responses are in progress.

Understanding of the mechanisms by which LDL is transported across endothelial layers provides the basis for developing methodologies that modulate retention and accumulation of lipid in the vessel wall. In contrast to the current focus in the pharmaceutical industry on lowering LDL level in blood to treat atherosclerosis (e.g. statins), the focus here is on methodologies that lower endothelial permeability to LDL.

The potential for pharmacological treatment to reduce LDL permeability will be enhanced by understanding the genes that control vascular permeability. Studies to address these issues have been initiated with collaborators at Rockefeller University, where the apo E knockout mouse, the standard animal model for atherosclerosis research, was developed.