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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We examined the effect of an inhibitor of DDAH1 (L\u2010257) on endothelial\u2010nitric oxide\u2010dependent 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\u2010257 at a concentration that did not alter cardiovascular haemodynamics on infarct volume and functional outcomes in mice after MCA occlusion (MCAo).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      In vitro, L\u2010257 impaired vasodilator responses of MCA (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      : ~50%), increased endothelial permeability (~1.5\u2010fold) and impaired endothelial outgrowth of MCA (~40%). In vivo, L\u2010257 (30\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) increased ADMA levels without affecting haemodynamics and resulted in larger infarcts and greater deficits after 40\u2010min transient MCAo (tMCAo). However, when mice were subjected to longer MCAo periods (65\u2010min tMCAo or permanent MCAo) to generate moderate\/severe insults, L\u2010257 did not significantly affect outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>DDAH1 contributes to the regulation of cerebrovascular endothelial\u2010nitric oxide\u2010regulated 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70556","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:02:40Z","timestamp":1785484960000},"page":"6422-6443","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct evidence implicating the asymmetrical dimethylarginine (ADMA)\u2010dimethylarginine dimethylaminohydrolase 1 (DDAH1) pathway in cerebrovascular dysfunction and stroke pathogenesis in mice"],"prefix":"10.1111","volume":"183","author":[{"given":"Arun","family":"Flynn","sequence":"first","affiliation":[{"name":"British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Riddell","sequence":"additional","affiliation":[{"name":"British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashton","family":"Bernard","sequence":"additional","affiliation":[{"name":"British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Haggarty","sequence":"additional","affiliation":[{"name":"Medical, Veterinary &amp; 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