The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature.

Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS

β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle

The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose of this study was to elucidate the specific effects of β-hydroxybutyrate (β-HB) on muscle cell mitochondrial physiology. In addition to increased cell viability, murine myotubes displayed beneficial mitochondrial changes evident in reduced H2O2 emission and less mitochondrial fission, which may be a result of a β-HB-induced reduction in ceramides. Furthermore, muscle from rats in sustained ketosis similarly produced less H2O2 despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity. In sum, these results indicate a general improvement in muscle cell mitochondrial function when β-HB is provided as a fuel