Accumulating evidence indicates that atherosclerotic lesion-prone (Evan's blue staining) areas of major arteries are coincident with ares exposed to chronic low shear, reversing flow patterns. Further, previous in vivo studies indicate that regional arterial endothelium chronically exposed to this flow environment resulting from either natural or surgically modified arterial geometry exhibit enhanced recruitment, adhesion, and transendothelial migration of monocytes, a hallmark of early atherogenesis. Unvortunately, it is unclear whether it is the low shear itself, the oscillatory nature of shear, or some other hemodynamic factor that is responsible for the alteration in monocyte recruitment by endothelium in these lesion-prone regions. Secondly, the intracellular signalling mechanisms responsible for transduction of the hemodynamic stimulus to this important alteration in endothelial biology remain undefined.
The Specific Aims are designed to first focus on identifying differences in monocyte adherence, MCP-1, and VCAM-1 expression in cultured human aortic endothelial cells exposed to the separated flow components of shear, pulsatility, and flow direction and, secondly, to examine the role of the phosphoinositide pathway related signal transduction molecules as mediators of shear stress induced alterations in monocyte recruitment, adhesion, and transendothelial migration. Within this overall objective, these aims are designed to: 1. To examine in vitro monocyte adherence to vascular endothelium and transendothelial migration under four different defined flow environment; including steady shear, pulsatile non-reversing, reversing, and purely oscillatory shear. 2. To characterize the cellular and molecular mechanisms mediating flow- induced alterations in monocyte-endothelial adherence and transendothelial migration. Specifically target will be MCP-1 and VCAM-1 gene and antigen expression. 3. To investigate signalling mechanisms which regulate gene expression and the secretion of molecules associated with flow-induced changes in endothelial-monocyte interactions with emphasis on those signal transduction molecules related to the phosphoinositide pathway.. A key aspect of this proposed effort is to study vascular endothelial biology under cell culture conditions engineered to include non-reversing and reversing pulsatile flow, and oscillatory flow which we believe to be more physiologic models. As part of this, studies will be performed both at The University of Texas Health Science Center at San Antonio and at Georgia Tech.
| Mohan, S; Mohan, N; Valente, A J et al. (1999) Regulation of low shear flow-induced HAEC VCAM-1 expression and monocyte adhesion. Am J Physiol 276:C1100-7 |
| Wiesner, T F; Berk, B C; Nerem, R M (1997) A mathematical model of the cytosolic-free calcium response in endothelial cells to fluid shear stress. Proc Natl Acad Sci U S A 94:3726-31 |
| Mohan, S; Mohan, N; Sprague, E A (1997) Differential activation of NF-kappa B in human aortic endothelial cells conditioned to specific flow environments. Am J Physiol 273:C572-8 |
