Abstract
Blood flow-induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis, but its role in EC responses to shear stress and focal atherosclerosis is unknown. To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease. The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by quantitative polymerase chain reaction and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness. TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus, pleiotropic functions of TWIST control vascular disease and development.
Highlights
Rationale: Blood flow–induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood
Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness
Atherosclerosis is promoted by systemic risk factors, it develops preferentially near branches and bends exposed to complex blood flow that generates shear stress with low-magnitude and significant variation in direction
Summary
Male mice between 2 and 3 months of age were used. Transgenic Rosa26-tdTomato mice[27] were crossed with endothelial-SCL-Cre-ERT mice containing a tamoxifen-inducible EC-specific Cre.[28] To activate Cre, tamoxifen was administered for 5 consecutive days (2 mg/mouse/d). Mice with conditional deletion of TWIST1 (TWIST1cKO) were generated by crossing Tie2-Cre– expressing mice (Jackson Laboratory stock 004128) with TWIST1 floxed mice (TWIST1flox|flox).[29] Mice with conditional EC deletion of GATA4 (called GATA4cKO) were generated by crossing endothelial-SCL-Cre-ERT mice with GATA4 floxed mice (GATA4flox|flox).
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