Maintenance of GLUT4 expression in smooth muscle prevents hypertension‐induced changes in vascular reactivity

Previous studies have shown that expression of GLUT4 is decreased in arterial smooth muscle of hypertensive rats and mice and that total body overexpression of GLUT4 in mice prevents enhanced arterial reactivity in hypertension. To demonstrate that the effect of GLUT4 overexpression on vascular responses is dependent on vascular smooth muscle GLUT4 rather than on some systemic effect we developed and tested smooth‐muscle‐specific GLUT4 transgenic mice (SMG4). When made hypertensive with angiotensin II, both wild‐type and SMG4 mice exhibited similarly increased systolic blood pressure. Responsiveness to phenylephrine, serotonin, and prostaglandin F2α was significantly increased in endothelium‐intact aortic rings from hypertensive wild‐type mice but not in aortae of SMG4 mice. Inhibition of Rho‐kinase equally reduced serotonin‐stimulated contractility in aortae of hypertensive wild‐type and SMG4‐mice. In addition, acetylcholine‐stimulated relaxation was significantly decreased in aortic rings of hypertensive wild‐type mice, but not in rings of SMG4 mice. Inhibition of either prostacylin receptors or cyclooxygenase‐2 reduced relaxation in rings of hypertensive SMG4 mice. Inhibition of cyclooxygenase‐2 had no effect on relaxation in rings of hypertensive wild‐type mice. Cyclooxygenase‐2 protein expression was decreased in hypertensive wild‐type aortae but not in hypertensive SMG4 aortae compared to nonhypertensive controls. Our results demonstrate that smooth muscle expression of GLUT4 exerts a major effect on smooth muscle contractile responses and endothelium‐dependent vasorelaxation and that normal expression of GLUT4 in vascular smooth muscle is required for appropriate smooth muscle and endothelial responses.e12299In the smooth muscle of aortae of hypertensive mice, expression of GLUT4 is decreased. Maintenance of aortic smooth muscle GLUT4 expression prevents hypertension‐mediated changes in vasomotor response. These effects include decreasing/preventing endothelial dysfunction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110755/1/phy212299.pd

Internationaler Steuerwettbewerb und Koordination der Steuersysteme

Die Arbeit untersucht die Wohlfahrtswirkungen des internationalen Steuerwettbewerbs sowie die Notwendigkeit und Möglichkeit einer Koordination der Steuersysteme im Bereich der direkten Steuern. Hierzu wird der Zusammenhang zwischen den Rahmenbedingungen, unter denen ein Steuerwettbewerb stattfindet, und dessen Rückwirkungen auf die Entscheidungen privater und staatlicher Akteure detailliert in einem einheitlichen Modellrahmen aufgezeigt. Dabei wird deutlich, dass negative Effizienzwirkungen des Steuerwettbewerbs Folge eines (n-1)-Problems sind. Weitere Schwerpunkte der Arbeit sind der Steuerwettbewerb zwischen Leviathan-Staaten sowie der Steuerwettbewerb und die Möglichkeit staatlicher Umverteilung bei internationaler Haushaltsmobilität. Ferner werden die Grenzen internationaler Kooperationen aufgezeigt und ein Lösungsansatz zur internationalen Kapitaleinkommensbesteuerung formuliert

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects

Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome‐wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS−/− mice receiving renin‐angiotensin‐aldosterone system (RAS)‐blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data analysis method, SOM, or self‐organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatic analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro‐inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAS exacerbated expression of genes related to inflammation and oxidant generation in peripheral nerves. The graded increase in inflammatory gene expression and decrease in development gene expression with DKD progression underline the potentially important role of these pathways in DKD pathogenesis. Since RAS blockers worsened this gene expression pattern in both DKD and DPN, it may partly explain the inadequate therapeutic efficacy of such blockers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167018/1/fsb221467_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167018/2/fsb221467.pd