Vascular nexus glia regulates vascular homeostasis and undergoes dynamic remodelling in deep vein thrombosis.

AIMS: The cardiovascular system is tightly regulated by the nervous system, yet while cardiac nexus glial cells are known modulators of physiology, the identity and functional significance of glial populations within the vasculature remain poorly defined. We hypothesized that a specialized population of vascular glial cells exists in the adventitia and undergoes molecular and morphological remodelling under pathological stress. METHODS AND RESULTS: By analysing human and murine single-cell RNA sequencing (scRNA-seq) datasets, we identified a conserved population of glial cells in large vessels. Using hGFAP-Cre;tdTomato reporter mice and the Mosaic Analysis with Double Markers (MADM) system, we characterized these vascular nexus glia (VNGs) as an extensive reticular network in the adventitia that are in contact with sympathetic nerve fibres. To investigate functional necessity, we ablated the epigenetic regulator Suz12 in the GFAP lineage, which impaired VNG development and triggered vascular metabolic dysregulation. Cross-tissue transcriptomic integration revealed that VNGs possess a unique metabolic and stress-response signature compared to other glial subtypes. In a murine deep vein thrombosis model, time-resolved scRNA-seq and tissue clearing mapped a biphasic phenotypic transition. During thrombosis development, VNGs exhibit profound plasticity, undergoing morphological retraction and transitioning from a neuro-supportive state to an activated profile characterized by extracellular matrix reorganization and pro-fibrotic signalling. CONCLUSION: Our study identifies VNGs as a ubiquitous glial network within the vascular adventitia essential for homeostatic maintenance. By uncovering their Suz12-dependent development and dynamic remodelling during thrombotic injury, we provide a new conceptual framework for the neuro-vascular interface in venous thromboembolic disease.