Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation. Sci Adv 2023 May 26;9(21):eade7280
Date
05/26/2023Pubmed ID
37235659Pubmed Central ID
PMC10219588DOI
10.1126/sciadv.ade7280Scopus ID
2-s2.0-85160378118 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
Author List
Huang L, Cheng F, Zhang X, Zielonka J, Nystoriak MA, Xiang W, Raygor K, Wang S, Lakshmanan A, Jiang W, Yuan S, Hou KS, Zhang J, Wang X, Syed AU, Juric M, Takahashi T, Navedo MF, Wang RAAuthor
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsArteries
Arteriovenous Malformations
Hydrogen Peroxide
Mice
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Nitroarginine
