Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis

A self-avoidance mechanism in patterning of the urinary collecting duct tree

BACKGROUND: Glandular organs require the development of a correctly patterned epithelial tree. These arise by iterative branching: early branches have a stereotyped anatomy, while subsequent branching is more flexible, branches spacing out to avoid entanglement. Previous studies have suggested different genetic programs are responsible for these two classes of branches. RESULTS: Here, working with the urinary collecting duct tree of mouse kidneys, we show that the transition from the initial, stereotyped, wide branching to narrower later branching is independent from previous branching events but depends instead on the proximity of other branch tips. A simple computer model suggests that a repelling molecule secreted by branches can in principle generate a well-spaced tree that switches automatically from wide initial branch angles to narrower subsequent ones, and that co-cultured trees would distort their normal shapes rather than colliding. We confirm this collision-avoidance experimentally using organ cultures, and identify BMP7 as the repelling molecule. CONCLUSIONS: We propose that self-avoidance, an intrinsically error-correcting mechanism, may be an important patterning mechanism in collecting duct branching, operating along with already-known mesenchyme-derived paracrine factors

Evolutionary Specialization of the Tongue in Vertebrates: Structure and Function

A conspicuous feature of extant tetrapods is a movable tongue that plays a role in food uptake, mastication, and swallowing. The tongue is a muscle mass covered by a mucosal sheath, but the tongues of amphibians, reptiles, birds, and mammals are diverse in general morphology and function. For example, in frogs and toads, a component of the musculus genioglossus serves as an intrinsic tongue muscle, with the anterior part of the tongue attached to the floor of the oral cavity. Nevertheless, these features of the tongue have allowed Anurans to diversify and disperse worldwide. On the other hand, the salamander tongue is connected to the oral cavity by a root with a cartilage or a bony skeleton, and it is mainly comprised of projection and retractor muscles. In this respect, the salamander tongue seems more similar to that of reptiles and mammals than to those of frogs and toads. The morphology and function of the tongues of some reptiles, such as chameleons, and some mammals, such as nectar-feeding bats, are examples of extreme specialization. Finally, the tongue has become almost vestigial in a few species of anurans, turtles, and birds. This review summarizes and discusses many specializations of tongue form and function among tetrapods