Dataset Information

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation.

ABSTRACT: Mechanisms underlying arteriovenous malformations (AVMs) are poorly understood. Using mice with endothelial cell (EC) expression of constitutively active Notch4 (Notch4*^EC), we show decreased arteriolar tone in vivo during brain AVM initiation. Reduced vascular tone is a primary effect of Notch4*^EC, as isolated pial arteries from asymptomatic mice exhibited reduced pressure-induced arterial tone ex vivo. The nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-l-arginine (L-NNA) corrected vascular tone defects in both assays. L-NNA treatment or endothelial NOS (eNOS) gene deletion, either globally or specifically in ECs, attenuated AVM initiation, assessed by decreased AVM diameter and delayed time to moribund. Administering nitroxide antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl also attenuated AVM initiation. Increased NOS-dependent production of hydrogen peroxide, but not NO, superoxide, or peroxynitrite was detected in isolated Notch4*^EC brain vessels during AVM initiation. Our data suggest that eNOS is involved in Notch4*^EC-mediated AVM formation by up-regulating hydrogen peroxide and reducing vascular tone, thereby permitting AVM initiation and progression.

SUBMITTER: Huang L

PROVIDER: S-EPMC10219588 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation.

Huang Lawrence L Cheng Feng F Zhang Xuetao X Zielonka Jacek J Nystoriak Matthew A MA Xiang Weiwei W Raygor Kunal K Wang Shaoxun S Lakshmanan Aditya A Jiang Weiya W Yuan Sai S Hou Kevin S KS Zhang Jiayi J Wang Xitao X Syed Arsalan U AU Juric Matea M Takahashi Takamune T Navedo Manuel F MF Wang Rong A RA

Science advances 20230526 21

Mechanisms underlying arteriovenous malformations (AVMs) are poorly understood. Using mice with endothelial cell (EC) expression of constitutively active Notch4 (Notch4*<sup>EC</sup>), we show decreased arteriolar tone in vivo during brain AVM initiation. Reduced vascular tone is a primary effect of Notch4*<sup>EC</sup>, as isolated pial arteries from asymptomatic mice exhibited reduced pressure-induced arterial tone ex vivo. The nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-l-arginine (L- ...[more]

PMID: 37235659

Similar Datasets

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

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation.

Publications

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets