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Endothelial cells are uniquely responsive to particular patterns of haemody-namic forces, especially shear stress. Under normal, physiological conditions, these forces serve as important signals to preserve the antithrombotic, anti-inflammatory, anti-oxidative stress and anti-apoptotic flow-responsive pheno-type of the vascular endothelium (Fig. 5). Critical testing of the "atheroprotec-tive gene hypothesis" will depend upon refinement of in vitro fluid mechanical models, genetic loss and gain-of-function experimental strategies in animal models, and the validation of expression patterns of candidate atheroprotective genes in the setting of human vascular pathobiology. The recent development of reliable methods for endothelial cell isolation from different regions of the pig aorta and the subsequent amplification of transcripts from a small number of cells and their analysis by complementary DNA (cDNA) microarrays hold much promise for the identification of atheroprotective genes from non-cultured endothelium (Passerini et al. 2004). Moreover, as we define in greater detail the components and mechanisms of mechano-homeostasis in vascular endothelium, targeting therapies to these mechanisms may prove to be an exciting and novel strategy for the treatment of diseases in which endothelial dysfunction plays a pathogenic role.

Atheroprotective Flow

Fig. 5 KLF2 is a key transcriptional integrator of the endothelial atheroprotective phenotype. The exposure of endothelial cells to atheroprotective flow leads to the upregulation of KLF2 expression. A similar upregulation of KLF2 is observed when endothelial cells are cultured in the presence of statins (see Fig. 4). The activation of this transcription factor (and others yet to be defined) evokes an "atheroprotective" endothelial cell phenotype. The identification of KLF2-dependent transcriptional programmes involved in the regulation of multiple endothelial functions (including inflammation, vascular tone and thrombosis) strongly suggests a critical role for this biomechanically regulated transcription factor in endothelial atheroprotection. CNP, C-type natriuretic peptide

Fig. 5 KLF2 is a key transcriptional integrator of the endothelial atheroprotective phenotype. The exposure of endothelial cells to atheroprotective flow leads to the upregulation of KLF2 expression. A similar upregulation of KLF2 is observed when endothelial cells are cultured in the presence of statins (see Fig. 4). The activation of this transcription factor (and others yet to be defined) evokes an "atheroprotective" endothelial cell phenotype. The identification of KLF2-dependent transcriptional programmes involved in the regulation of multiple endothelial functions (including inflammation, vascular tone and thrombosis) strongly suggests a critical role for this biomechanically regulated transcription factor in endothelial atheroprotection. CNP, C-type natriuretic peptide

Acknowledgements We thank members of the Gimbrone and Garcfa-Cardena Laboratories for their conceptual input and experimental collaboration, especially Guohao Dai, Kush M. Parmar, Harry B. Larman, Yvonne Ou, Jason Comander, Yuzhi Zhang, Eric T. Wang and Keith R. Anderson. The authors also wish to acknowledge the multiple contributions from past members of the Vascular Research Division at the Brigham and Women's Hospital, and the ongoing collaboration of Drs. C.F. Dewey and Roger Kamm in the Fluid Mechanics Laboratory at MIT, and Dr. Mukesh Jain and colleagues in the Cardiovascular Division at the Brigham and Women's Hospital. The original research studies summarised here were supported primarily by grants from the National Heart, Lung and Blood Institute (P50-HL56985, R37-HL51150 and R01-HL076686).

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