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

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.

adventitial fibroblasts; autophagy; discoidin domain receptor 2; phenotypic switch.