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Homeostatic Role of Toll-like Receptor 4 in the Endothelium and Heart

Cardiac, Vascular, and Inflammation Research, William Harvey Institute, Queen Mary's University of London, Charterhouse Square, London, EC1M 6BQ, l.harrington{at}imperial.ac.uk

Elizabeth Belcher, PhD

Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY

Laura Moreno, PhD

Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY

Martin J. Carrier, PhD

Cardiac, Vascular, and Inflammation Research, William Harvey Institute, Queen Mary's University of London, Charterhouse Square, London, EC1M 6BQ

Jane A. Mitchell, PhD

Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, j.a.mitchell{at}imperial.ac.uk

Toll-like receptor 4 (TLR4) is a pattern recognition receptor for lipopolysaccharide from Gram negative bacteria and thus is integral to the innate immune response in mammals. In addition, TLR4 is associated with atherosclerosis in murine models. The current study shows that blood vessels from TLR4^-/- mice have an intact endothelial layer and comparable expression of nitric oxide synthase 3 protein. However, endothelium-dependent dilation in response to acetylcholine in vessels from TLR4^-/- mice is greatly reduced. By contrast, endothelium-independent smooth muscle dilation in response to sodium nitroprusside in vessels from TLR4^-/- mice remains intact. Furthermore, this study shows that hearts from TLR4^-/- mice display signs of left ventricular dilation. In contrast to results in vessels from TLR4^-/- mice, endothelium-dependent responses to acetylcholine in vessels from TLR2^-/- mice remain intact. These observations illustrate a novel role for TLR4 in the homeostatic control of a functional endothelium and, thereby, cardiovascular health.

Key Words: TLR4 • endothelium • dilation • hypertrophy • artery

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