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This study investigates the interactions between cyclooxygenase (COX-2) and vascular smooth muscle cell (VSMC) phenotypic switching, the two important coupling mechanisms of the vasculature on arterial remodeling in response to high laminal shear stress. High aortic blood flow was induced by creating a fistula in the abdominal aorta and the adjacent IVC of anesthetized rats. Celecoxib, a selective COX-2 inhibitor (25 mg/kg/day), was fed in the chow, and animals were killed 8 weeks later. Blood flow, vasoreactivity and morphological changes in the aorta proximal to the fistula were measured. Concentrations of collagen, expression of desmin and smooth muscle myosin heavy chain (SM-MHC)-II in the aorta were determined. Celecoxib significantly increased aortic blood flow and reduced the contraction responses of aorta. Decreased medial thickness, presence of intimal thickening and derangement of elastic lamina were found in the aortic section of celecoxib-treated animals. Celecoxib significantly reduced the tissue content of collagen and upregulated expression of SM-MHC-II and desmin in the high-flow aorta. Inhibition of COX-2 enzymatic activity in the aorta exposed to higher blood flow resulted in increased blood flow and vascular remodeling. These functional changes were accomplished by VSMC phenotypic switching and reduced biosynthesis of collagen.

Objective: The blood flow in the arteriovenous (AV) fistula is significantly reduced in diabetic patients. Statins are known to mediate pleiotropic effects in the vascular endothelium and attenuate inflammatory responses. This study tested the vascular protective effect of rosuvastatin in an experimental model of AV fistula. Methods: One week after the induction of diabetes mellitus (DM) in rats, a fistula was created in the abdominal aorta and inferior vena cava. Rats received placebo or rosuvastatin (15 mg/kg/day) in chow for 2 weeks. The blood flow in the venous segments of the fistula was measured. The expression of proinflammatory genes and the generation of superoxide in the venous fistula were examined. Results: The blood flow and luminal diameter of the AV fistula was significantly enhanced in animals treated with rosuvastatin. Rosuvastatin attenuated the expression of inducible nitric oxide synthase, NADPH oxidase, and monocyte chemotactic protein-1 in the fistula. The levels of superoxide anions and proinflammatory cytokines were also suppressed in rosuvastatin-treated animals. Neointimal formation in the AV fistula was not affected following treatment with rosuvastatin. Conclusions: We demonstrated that rosuvastatin improves luminal dilatation and blood flow in the AV fistula of subjects with DM. These vascular protective effects of rosuvastatin are most likely mediated by the attenuation of proinflammatory activities in the remodeled vasculature. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: This study investigates the pathogenesis of arteriovenous (AV) fistula failure in patients with diabetes mellitus (DM) and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. Methods: DM was induced in rats by a single injection of streptozotocin. One week later, a fistula was created in the descending aorta and the adjacent inferior vena cava (aortocaval [AC] fistula). Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. Blood flow in the aortic segments of the fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined 2 weeks after creation of the AC fistulas using flow cytometry. Vascular function of the AC fistulas was assessed by isometric force testing. The expression of proinflammatory genes and generation of superoxide anions in the fistulas were examined. Results: The number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased the number of circulating EPCs. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated after treatment with rosuvastatin. Rosuvastatin also attenuated the expression of inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidase and generation of superoxide anions in the fistula tissues isolated from diabetic rats. Conclusions: We provide the first evidence demonstrating that rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with DM by attenuating the activity of proinflammatory genes and generation of superoxide anions in the remodeled vasculature. [ABSTRACT FROM AUTHOR]