DDR2-mediated autophagy inhibition contributes to angiotensin II-induced adventitial remodeling

Abstract

Aims: Adventitial remodelling in hypertension is characterized by a transformation of adventitial fibroblasts (AFs) into myofibroblasts. Previous studies have highlighted the crucial role of discoidin domain receptor 2 (DDR2) in vascular remodelling. Since DDR2-sustained tyrosine phosphorylation activates PI3K, which may inhibit autophagy through the mTOR signalling pathway, we aimed to investigate whether DDR2 contributes to mTOR-mediated autophagy suppression and subsequently promotes AFs transformation and adventitial remodelling.

Methods and results: Single-cell RNA sequencing revealed that DDR2 was upregulated in adventitial fibroblasts (AFs) in angiotensin II (Ang II, 1000 ng/min/kg) administrated wild-type (WT) mice. In AFs, rapamycin, an autophagy agonist, significantly attenuated Ang II-induced autophagy suppression and phenotype switching, whereas the autophagy inhibitor chloroquine (CQ) exacerbated these effects. DDR2 inhibition significantly alleviated PI3K/Akt/mTOR pathway-mediated autophagy suppression and subsequently inhibited AFs phenotypic switching. Conversely, DDR2 overexpression aggravated autophagy suppression and AFs phenotypic switching. Consistent with the cellular findings, prophylactic administration of rapamycin (4 mg/kg/d) or conditional knockout of Ddr2 in mice ameliorated autophagy suppression, AFs differentiation and adventitial remodelling in vivo.

Conclusion: DDR2 serves as a critical mediator of autophagy suppression during Ang II-induced phenotypic transformation of AFs and adventitial remodelling. Targeting DDR2 signalling attenuates autophagy dysfunction and inhibits AFs activation, thereby mitigating pathological adventitial remodelling. These findings highlight DDR2 as a potential therapeutic target for preventing conditions driven by aberrant adventitial remodelling.

Keywords

adventitial fibroblasts / autophagy / discoidin domain receptor 2 / phenotypic switch

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.