1. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
2. Mario Negri Institute for Pharmacological Research and FIRC Institute of Molecular Oncology, Department of Biomolecular and Biotechnological Sciences, Faculty of Sciences, University of Milan, 20139 Milan, Italy
3. Department of Physics, University of California at San Diego, La Jolla, California 92093, USA
4. Theodor Kocher Institute, University of Bern, Freiestr. 1, CH-3012 Bern, Switzerland
5. Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA
6. Departments of Microbiology and Biomedical Engineering, Cardiovascular Research Center, Mellon Prostate Cancer Research Center, University of Virginia, 415 Lane Road, Charlottesville, Virginia 22908, USA
7. †Present address: Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, 6312 Medical Biomolecular Research Building, 103 Mason Farm Road, Chapel Hill, North Carolina 27599, USA

Correspondence to: Martin Alexander Schwartz^1,6 Correspondence and requests for materials should be addressed to M.A.S. (Email: maschwartz@virginia.edu).

Abstract

Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis¹, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression^{2, 3, 4}. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-B and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.

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