GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism

Wei Xie; Chen Ning; Chen Lu; Dongjin Wang; Shuang Zhao; Tianyu Song; Hailong Cao

doi:10.1172/jci.insight.203575

GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism

Wei Xie,¹ Chen Ning,² Chen Lu,¹ Dongjin Wang,³ Shuang Zhao,⁴ Tianyu Song,⁵ and Hailong Cao¹

Published April 23, 2026 - More info

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Abstract

Aortic dissection (AD) is a catastrophic vascular emergency with high mortality, and current pharmacologic interventions to prevent its progression are limited. Vascular smooth muscle cells (VSMCs) undergo a pathological phenotypic switch from a contractile to a synthetic state during AD, compromising aortic wall integrity; however, the underlying metabolic mechanisms remain poorly understood. In this study, we performed integrative transcriptomic analyses and identified glutaminase 1 (GLS1) as a key regulator of VSMC phenotypic switching in AD. GLS1 expression was significantly downregulated in VSMCs from both human AD aortic tissues and mouse models. Functionally, GLS1 deficiency promoted PDGF-BB–induced VSMC dedifferentiation in vitro. Smooth muscle cells specific Gls1 knockout (Gls1^SMKO) mice exhibited aggravated AD upon BAPN treatment, whereas VSMCs specific GLS1 overexpression improved the contractile phenotype and reduced AD incidence. Mechanistically, GLS1 downregulation impaired glutamate metabolism, leading to reduced levels of glutathione and α-ketoglutarate. This metabolic disruption promoted reactive oxygen species accumulation and mitochondrial dysfunction, ultimately triggering VSMC phenotypic switching. Furthermore, we found that GLS1 transcription was repressed by retinoic acid receptor-α (RARα). Pharmacologic inhibition of RARα with AR7 restored GLS1 expression, ameliorated VSMC phenotypic switching, and conferred protection against AD. These findings reveal a critical role of GLS1-mediated glutamate metabolism in VSMC phenotypic switching and suggest a promising therapeutic strategy for AD.

GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism

Wei Xie,¹ Chen Ning,² Chen Lu,¹ Dongjin Wang,³ Shuang Zhao,⁴ Tianyu Song,⁵ and Hailong Cao¹

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GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism

Wei Xie,1 Chen Ning,2 Chen Lu,1 Dongjin Wang,3 Shuang Zhao,4 Tianyu Song,5 and Hailong Cao1

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Wei Xie,¹ Chen Ning,² Chen Lu,¹ Dongjin Wang,³ Shuang Zhao,⁴ Tianyu Song,⁵ and Hailong Cao¹