TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis.

RATIONALE: 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. OBJECTIVE: Investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis, and compare TWIST function in vascular development and disease. METHODS AND RESULTS: 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 qPCR 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. CONCLUSIONS: 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 as well as development

CP Violation in the B System and Relations to K→πννˉK\to\pi\nu\bar{\nu} Decays

A review of CP violation in the $B$ system and strategies to determine the unitarity triangle of the CKM matrix is given. We begin with an introduction to the description of CP violation in the Standard Model of electroweak interactions, and discuss the basic features of the theoretical framework to deal with non-leptonic B decays, which play the main role in this review. After a brief look at CP violation in the kaon system and a discussion of the rare decays $K^+\to\pi^+\nu\bar{\nu}$ and $K_L\to\pi^0\nu\bar{\nu}$, we turn to the formalism of $B^0_{d,s}$--$\bar{B^0_{d,s}}$ mixing, allowing us to explore important $B$-factory benchmark modes and the $B_s$-meson system. We then focus on charged B decays, $B\to\pi K$ modes and the phenomenology of $U$-spin related B decays, including the $B_d\to\pi^+\pi^-$, $B_s\to K^+K^-$ system. Finally, we discuss a particularly simple -- but very predictive -- scenario for new physics, which is provided by models with ``minimal flavour violation''. In this framework, various bounds can be derived and interesting connections between the $B$ system and the rare kaon decays $K^+\to\pi^+\nu\bar{\nu}$ and $K_L\to\pi^0\nu\bar{\nu}$ arise.Comment: LaTeX, 173 pages, 38 figures, to appear in Physics Reports (Habilitation Thesis, Hamburg Univ., July 2001