ST3GAL1-mediated α-2,3 sialylation restrains CD105-TGFβRII signaling to attenuate EndMT-driven atherosclerosis.

Background

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Aims

Endothelial-to-mesenchymal transition (EndMT) contributes to atherosclerotic plaque progression. Although endothelial sialylation is essential for vascular homeostasis, its role in EndMT remains poorly understood. This study investigated the role and underlying mechanism of α-2,3 sialylation in EndMT and atherosclerosis.

Methods

We investigated endothelial α-2,3 sialylation and its regulation during TGF-β-induced EndMT using endothelial cell models. ChIP-qPCR and promoter analyses were performed to determine SMAD2/3-dependent transcriptional regulation of ST3GAL1. IP-MS combined with biochemical validation was used to identify and characterize ST3GAL1 substrates. The functional role of the ST3GAL1-CD105 axis was further examined in vitro and in vivo.

Results

TGF-β-induced EndMT was accompanied by selective reduction of α-2,3 sialylation and downregulation of ST3GAL1. Mechanistically, TGF-β directly repressed ST3GAL1 transcription through SMAD2/3 binding to its promoter. ST3GAL1 overexpression restored α-2,3 sialylation and inhibited EndMT in an α-2,3-sialyltransferase activity-dependent manner. CD105 was identified as a major substrate of ST3GAL1, and its α-2,3 sialylation was reduced during EndMT. ST3GAL1-mediated α-2,3 sialylation limited CD105-TGFβRII association, thereby restraining SMAD2/3 activation. In vivo, endothelial-specific ST3GAL1 overexpression or CD105 knockdown inhibited EndMT and attenuated atherosclerotic lesion development.

Conclusions

The ST3GAL1-CD105 sialylation axis is a key regulator of TGF-β-driven EndMT and represents a potential therapeutic target for atherosclerosis.