Research Summary

Laboratory investigation includes the fundamental aspects of fluid mechanics and mass transport that are involved in the modulation of mammalian cell function. Special attention is given to the cells in the arterial circulation with major research efforts directed to identify the mechanistic links between hemodynamics and vascular biology.

A main objective is to develop experimental and mathematical models that, in relation to the flow characteristic, describe the dynamics of cell behavior and cell interactions occurring at the arterial surface in early atherosclerosis. Focus is on the identification of cellular and molecular mechanisms by which specific flow parameters regulate endothelial function, contributing to localized vessel wall remodeling and the development of atherosclerotic lesions.

Our studies combine mammalian cell models, experimental fluid dynamics, and biochemical/molecular techniques. The detailed characterization of the cell mechanical environment is obtained using experimental, analytical, and numerical simulation techniques.

The novelty of our research approach resides on the fact that the biological emphasis is in cell dysfunction and that the fluid dynamics (and convective mass transport) emphasis is in the complex flows found at atherogenesis-prone sites of the human vasculature.

Research work on endothelial intercellular communication has been conducted in close collaboration with Dr. Polacek and Dr. Davies from the Institute for Medicine and Engineering at Penn. We have reported the first in vitro study on gap junctional regulation by fluid forces and demonstrated that spatial gradients in fluid shear stress (associated with disturbed flow regions) induce local changes in endothelial gap junction-mediated intercellular communication. The results demonstrate that gene expression, protein organization, and function of the gap junctional protein connexin 43 is regionally mapped to hemodynamic forces.

More recently in collaboration with the IME at Penn (Dr. D. Polacek and Dr. P.F. Davies) we are investigating the hypothesis that within any defined region of the vessel wall there is significant heterogeneity of endothelial signaling and gene expression regulated by differential shear stress from cell to cell. This study involves the analysis of gene expression in single cells, and group of cells, removed from precise hemodynamic locations in vitro and in vivo. The expression of known shear stress-responsive genes is being evaluated and new hemodynamic genes are expected to be identified. Our in vitro flow studies consider the complex spatial and temporal flow characteristics found in regions prone to atherosclerosis (flow disturbance). Hemodynamic gene expression is being studied based on spatial and temporal variations in shear stress defined at the local cell surface. Well-characterized and precise experimental models of spatially defined flow are combined with regional and single-cell gene-expression profiling to investigate the relationships linking hemodynamics to vessel-wall pathobiology.

(Detailed research information can be found on Dr. DePaola's homepage.)