The role of SUMOylation in the neurovascular dysfunction after acquired brain injury

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TL;DR

This review examines the role of SUMOylation, a post-translational protein modification, in neurovascular dysfunction following acquired brain injury (ABI). It finds that SUMOylation has both protective and detrimental effects on key components of the neurovascular unit, including endothelial cells, neurons, microglia, and astrocytes, as well as on vascular remodeling. The clinical significance lies in identifying SUMOylation as a potential therapeutic target for mitigating secondary brain injury and promoting recovery after ABI.

Full summary

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**Background:** Acquired brain injury (ABI), encompassing traumatic brain injury (TBI) and non-TBI (e.g., stroke), leads to significant neurovascular dysfunction, including blood-brain barrier (BBB) disruption, neurovascular unit (NVU) impairment, and altered cerebral blood flow. These changes drive secondary injury cascades such as inflammation, oxidative stress, and excitotoxicity. SUMOylation, a reversible post-translational modification involving the attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, regulates protein localization, stability, and interactions. This review synthesizes current evidence on how SUMOylation influences neurovascular components and remodeling after ABI.

**Methods:** This is a narrative review that summarizes findings from preclinical studies (animal models and in vitro experiments) investigating the role of SUMOylation in ABI-related neurovascular dysfunction. The authors systematically discuss the effects of SUMOylation on endothelial cells, neurons, microglia, astrocytes, pericytes, vascular smooth muscle cells (VSMCs), and angiogenesis, drawing on published literature.

**Key Results:** The review highlights that SUMOylation exerts dual roles depending on the cellular context and specific molecular targets. In endothelial cells, SUMOylation of Trx2 inhibits senescence, while SUMOylation of FAK K152 promotes activation and senescence. DeSUMOylation of GATA2 by SENP1 aggravates inflammation, whereas SUMOylation of NLRP3 inhibits inflammation. SUMOylation of ATF3 accelerates endothelial dysfunction, and SUMOylation of ERK5 promotes inflammation. In neurons, SUMOylation (especially via SUMO2/3 and Ubc9) is generally neuroprotective, blocking oxidative stress and protecting against ischemia. Knockout of SUMO2 in neurons impairs cognitive function. In microglia, SUMOylation of Annexin-A1 improves neurological function after ischemia, while SENP6 downregulation reduces infarct size. However, SENP6 overexpression can also prevent neuroinflammation induced by alcohol. In astrocytes, guanosine enhances SUMOylation to exert neuroprotection. In pericytes, SENP1 deletion worsens ischemic injury. For VSMCs, SUMOylation of KLF4, PPARγ, and RhoGDI promotes proliferation and migration, while SENP3 promotes VSMC proliferation and arterial remodeling. In angiogenesis, SUMOylation of VEGFR2 and Notch1 regulates vessel formation; loss of SENP1 hinders pathological angiogenesis, while SENP2 deficiency improves cardiac angiogenesis after myocardial infarction via AKT SUMOylation.

**Clinical Implications:** The findings suggest that SUMOylation is a critical modulator of neurovascular dysfunction after ABI, with both protective and detrimental effects. Targeting specific SUMOylation pathways (e.g., enhancing neuroprotective SUMOylation in neurons or inhibiting pro-inflammatory SUMOylation in endothelial cells) could offer novel therapeutic strategies. However, the complexity and context-dependence of SUMOylation effects necessitate careful targeting to avoid adverse outcomes. The review underscores the need for further research to clarify causal relationships and develop selective modulators for clinical translation.