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Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans.

ABSTRACT: Nitric oxide (NO), produced by endothelial cells, is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOS). NO is known to reduce the ratio of receptor activator of nuclear factor KappaB (RANKL)/osteoprotegerin (OPG), leading to decreased osteoclastogenesis and a reduction in bone resorption. Endothelial nitric oxide synthase (eNOS or NOS3) is the predominant constitutive isoform of nitric NOS within bone. Recently, a NOS3 polymorphism, Glu298Asp, previously implicated in osteoporosis, failed to demonstrate an association with bone mineral density (BMD), although there was some indication of an association with selected geometry indices. Since a single polymorphism does not capture all of the potential variants in a given gene, we investigated a broader coverage of the NOS3 gene with bone density/ultrasound and geometry indices in a sample of unrelated individuals from the Framingham Offspring Study. Our results indicated that the Glu298Asp polymorphism was not associated with BMD but suggested some haplotype-based associations in the linkage disequilibrium (LD) region that included the Glu298Asp polymorphism with several geometry indices. Although our findings exhibited several associations with selected bone density/ultrasound and geometry indices, the nominally significant associations are regarded as primarily hypothesis generating and suggest that replication in other samples is needed. Thus, NOS3 genetic variation does not appear to be a major contributor to adult bone density/ultrasound and geometry in our sample.

SUBMITTER: Cho K

PROVIDER: S-EPMC2386517 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans.

Cho K K Demissie S S Dupuis J J Cupples L A LA Kathiresan S S Beck T J TJ Karasik D D Kiel D P DP

Bone 20070929 1

Nitric oxide (NO), produced by endothelial cells, is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOS). NO is known to reduce the ratio of receptor activator of nuclear factor KappaB (RANKL)/osteoprotegerin (OPG), leading to decreased osteoclastogenesis and a reduction in bone resorption. Endothelial nitric oxide synthase (eNOS or NOS3) is the predominant constitutive isoform of nitric NOS within bone. Recently, a NOS3 polymorphism, Glu298Asp, previously implicated ...[more]

PMID: 17980690

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Project description:BackgroundArteriovenous fistula (AVF) maturation failure is a significant clinical problem in the hemodialysis population. Geometric parameters of human AVFs were associated with AVF development, but causative studies are lacking. We characterized mouse AVF geometry using endothelial nitric oxide synthase (NOS3) mouse models.MethodsCarotid-jugular AVFs were created in NOS3 overexpression (OE), knockout (KO), and wild type (WT) mice. At 7 and 21 days postcreation, black-blood magnetic resonance images of AVFs were acquired and used to build three-dimensional reconstructions of AVF lumens. We used these reconstructions to calculate the lumen area, lumen centerline, and centerline-derived parameters: anastomosis angle, tortuosity, nonplanarity angle, and location of maximal distance between the feeding artery and AVF vein. Inter- and intrauser variabilities were also determined.ResultsWhen all mice were considered, increased minimum AVF venous lumen area was accompanied by increased venous tortuosity and increased distance between the artery and vein, with both remaining in-plane with the anastomosis. At day 7, the lumen area of AVFs from all strains was 1.5- to 2.5-fold larger than native veins. Furthermore, at day 21, AVF lumen in NOS3 OE (4.04±1.43 mm2) was significantly larger than KO (2.74±1.34 mm2) (P<0.001) and WT (2.94±1.30 mm2) mice (p<0.001). At day 21, the location of maximal artery-vein distance on the vein was further away from the anastomosis in OE (4.49±0.66 mm) than KO (2.87±0.38 mm) (p=0.001). Other geometric parameters were not significantly different between mouse strains or time points. Inter- and intrauser variabilities were small, indicating the reliability and reproducibility of our protocol.ConclusionsOur study presents a detailed characterization of mouse AVF geometry, and a robust protocol for future mechanistic studies to investigate the role of molecular pathways in AVF geometry. Identifying a geometry related to desired AVF remodeling can help inform surgery to enhance AVF maturation.

Dataset Information

Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans.

Publications

Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans.

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