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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1757.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Laminar Shear Stress Regulates Endothelial Kinin B1 Receptor Expression and Function

Potential Implication in Atherogenesis

Johan Duchene; Cécile Cayla; Sandrine Vessillier; Ramona Scotland; Kazuo Yamashiro; Florence Lecomte; Irfan Syed; Phuong Vo; Alessandra Marrelli; Costantino Pitzalis; Francesco Cipollone; Joost Schanstra; Jean-Loup Bascands; Adrian J. Hobbs; Mauro Perretti; Amrita Ahluwalia

From the William Harvey Research Institute (J.D., C.C., S.V., R.S., K.Y., F.L., I.S., P.V., A.M., C.P., M.P., A.A.), Barts and The London School of Medicine & Dentistry, London, UK; the Italian Society for the Study of Atherosclerosis, Abruzzo Section (F.C.), Italy; the Centre for Pharmacology, Inserm, U858/I2MR, Department of Renal and Cardiac Remodeling (J.S., J.-L.B.), Université Toulouse III Paul Sabatier, Institut de Médecine Moléculaire de Rangueil, Toulouse, F-31000 France; and Pharmacology (A.J.H.), University College London, UK.

Correspondence to Prof Amrita Ahluwalia, Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Charterhouse Square, London EC1M 6BQ, UK. E-mail a.ahluwalia{at}qmul.ac.uk

Objective— The proinflammatory phenotype induced by low laminar shear stress (LSS) is implicated in atherogenesis. The kinin B1 receptor (B1R), known to be induced by inflammatory stimuli, exerts many proinflammatory effects including vasodilatation and leukocyte recruitment. We investigated whether low LSS is a stimulus for endothelial B1R expression and function.

Methods and Results— Human and mouse atherosclerotic plaques expressed high level of B1R mRNA and protein. In addition, B1R expression was upregulated in the aortic arch (low LSS region) of ApoE^–/– mice fed a high-fat diet compared to vascular regions of high LSS and animals fed normal chow. Of interest, a greater expression of B1R was noticed in endothelial cells from regions of low LSS in aortic arch of ApoE^–/– mice. B1R was also upregulated in human umbilical vein endothelial cells (HUVECs) exposed to low LSS (0 to 2 dyn/cm²) compared to physiological LSS (6 to 10 dyn/cm²): an effect similarly evident in murine vascular tissue perfused ex vivo. Functionally, B1R activation increased prostaglandin and CXCL5 expression in cells exposed to low, but not physiological, LSS. IL-1β and ox-LDL induced B1R expression and function in HUVECs, a response substantially enhanced under low LSS conditions and inhibited by blockade of NFB activation.

Conclusion— Herein, we show that LSS is a major determinant of functional B1R expression in endothelium. Furthermore, whereas physiological high LSS is a powerful repressor of this inflammatory receptor, low LSS at sites of atheroma is associated with substantial upregulation, identifying this receptor as a potential therapeutic target.

Low laminar shear stress (LSS) underlies the proinflammatory processes in atherogenesis. Herein, we demonstrate that whilst physiological LSS represses inflammatory kinin B1 receptor (B1R) expression/function, low atherogenic LSS is associated with profound upregulation of both in atherosclerosis in both humans and animal models, highlighting B1R as an exciting potential therapeutic target.

Key Words: atherosclerosis • laminar shear stress • inflammation • kinin B1 receptor