Direct evidence implicating the asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase 1 (DDAH1) pathway in cerebrovascular dysfunction and stroke pathogenesis in mice.

Authors

Arun Flynn, Alexandra Riddell, Ashton Bernard, Jennifer Haggarty, Stefan Weidt, Jawza Alenazi, Erika Trabold, Delyth Graham, Laura B Dowsett, James Leiper, Alyson A Miller

Published in

British journal of pharmacology. Jul 31, 2026. Epub Jul 31, 2026.

Abstract

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), whereas dimethylaminohydrolase 1 (DDAH1) is primarily responsible for its metabolism. However, the roles of DDAH1 in cerebrovascular regulation are poorly understood. Furthermore, despite evidence that elevated ADMA levels are associated with worse ischaemic stroke outcomes, there is a paucity of data showing causality. Therefore, this study aimed to address these knowledge gaps.
We examined the effect of an inhibitor of DDAH1 (L-257) on endothelial-nitric oxide-dependent vasodilator responses of mouse middle cerebral arteries (MCA), permeability of immortalised human cerebral endothelial cells and angiogenic activity of MCA. To test for a causal relationship between ADMA and stroke pathogenesis, we examined the effect of L-257 at a concentration that did not alter cardiovascular haemodynamics on infarct volume and functional outcomes in mice after MCA occlusion (MCAo).
In vitro, L-257 impaired vasodilator responses of MCA (R_max: ~50%), increased endothelial permeability (~1.5-fold) and impaired endothelial outgrowth of MCA (~40%). In vivo, L-257 (30 mg·kg^-1) increased ADMA levels without affecting haemodynamics and resulted in larger infarcts and greater deficits after 40-min transient MCAo (tMCAo). However, when mice were subjected to longer MCAo periods (65-min tMCAo or permanent MCAo) to generate moderate/severe insults, L-257 did not significantly affect outcomes.
DDAH1 contributes to the regulation of cerebrovascular endothelial-nitric oxide-regulated physiological processes in vitro. Furthermore, we provide direct evidence linking elevated ADMA levels and stroke pathogenesis; however, this relationship may be dependent on initial stroke severity.

PMID:
42533770
Bibliographic data and abstract were imported from PubMed on 31 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.