The goal of this proposal is to better understand how an endothelial cell transduces a physical force (shear stress) into a chemical signal (nitric oxide, NO). Shear-dependent production of NO in endothelial cells is well characterized in numerous vascular beds. However, the underlying .mechanisms by which NO is formed are not completely defined. Furthermore, in some cases where mechanisms are characterized, the endothelial cell source and/or the shear stress stimulus employed render the results irrelevant to the in vivo laminar flow environment where flow- dependent contributions to vascular tone are vital. Preliminary evidence suggests that endothelial K+ channels are activated in response to increased shear stress, which may contribute to membrane hyperpolarization and NO formation. Increases in [Ca2+], are also observed after raising shear stress, but the Ca2+ source/pathway is not well understood. Therefore, the specific aims of this proposal are to: 1) determine the role of ion channels in shear induced Ca2+-dependent NO production, and 2) investigate potential pathways initiated by NO formation that contribute to the shear-dependent endothelial response. Collectively, these experiments will enhance our understanding of cellular mechanisms by which endothelial NO is formed during shear stress, and contribute to the foundation for future studies that may develop new pharmacological agents/strategies to treat cardiovascular diseases such as hypertension.
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| Nurkiewicz, Timothy R; Porter, Dale W; Barger, Mark et al. (2006) Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure. Environ Health Perspect 114:412-9 |
| Marvar, Paul J; Nurkiewicz, Timothy R; Boegehold, Matthew A (2005) Reduced arteriolar responses to skeletal muscle contraction after ingestion of a high salt diet. J Vasc Res 42:226-36 |
| Nurkiewicz, Timothy R; Porter, Dale W; Barger, Mark et al. (2004) Particulate matter exposure impairs systemic microvascular endothelium-dependent dilation. Environ Health Perspect 112:1299-306 |
