Key result
Targeting DDR1 reduces aortic THBS1, vascular stiffening, and atherosclerosis in CKD models.
Why the study?
Chronic kidney disease is linked to arterial stiffening and atherosclerosis, but how stiffness promotes atherogenesis remained unclear. Whether DDR1-mediated mechanosensation links arterial stiffness to vascular smooth muscle cell-endothelial paracrine communication in CKD-related atherosclerosis was unknown.
Does targeting DDR1-mediated mechanosensation (via SMC-specific Ddr1 deletion or DEPTAC) reduce THBS1 expression, vascular stiffening, and atherosclerotic burden in a CKD-hyperlipidemia mouse model?
Does targeting DDR1-mediated mechanosensation (via SMC-specific Ddr1 deletion or DEPTAC) reduce THBS1 expression, vascular stiffening, and atherosclerotic burden in a CKD-hyperlipidemia mouse model?
DDR1-dependent mechanosensing in vascular smooth muscle cells drives stiffness-induced paracrine THBS1 signaling to the endothelium to promote CKD-accelerated atherosclerosis, identifying mechanical DDR1 activation as a potential therapeutic target.
DDR1 targeting attenuates atherosclerosis in CKD mouse models; leaves open translation to human outcomes.
BACKGROUND: Chronic kidney disease (CKD) increases cardiovascular risk and is linked to arterial stiffening and atherosclerosis. How stiffness promotes atherogenesis remains unclear. DDR1 (discoidin domain receptor 1), a mechanosensory tyrosine kinase receptor, has been implicated in force-regulated arterial remodeling. We investigated whether DDR1-mediated mechanosensation links arterial stiffness to vascular smooth muscle cell (SMC)-endothelial paracrine communication in CKD-related atherosclerosis. METHODS: Single-cell RNA sequencing, secretome proteomics, and bulk RNA sequencing were integrated with stiffness-controlled models, endothelial assays, and a CKD-hyperlipidemia mouse model. SMC-specific Ddr1 deletion and a DDR1 dephosphorylation-targeting chimera (DEPTAC) were evaluated in vivo. Plasma TSP-1 (thrombospondin-1) levels were quantified in a CKD clinical cohort and analyzed in relation to renal function and atherosclerosis severity. RESULTS: CKD-associated vascular stiffening coincided with SMC phenotypic switching and enhanced THBS signaling. Multiomics integration identified THBS1 as a stiffness-induced SMC secretory effector. Stiff matrices increased SMC THBS1 secretion, promoting endothelial proliferation, migration, and leukocyte adhesion; these effects were attenuated by THBS1 knockdown. DDR1 coupled matrix stiffness cues to THBS1 expression by regulating its transcription via a tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon-FOXO3 (forkhead box O3) axis. Vascular SMC-specific Ddr1 deletion reduced aortic THBS1 levels, vascular stiffening, and atherosclerotic burden. DEPTAC suppressed aberrant DDR1 phosphorylation, reduced THBS1, and ameliorated vascular stiffening and atherosclerosis. Plasma THBS1 increased with CKD severity and correlated with atherosclerosis. CONCLUSIONS: DDR1-dependent mechanosensing in SMCs drives stiffness-induced paracrine signaling to endothelium via THBS1, promoting CKD-accelerated atherosclerosis. Targeting mechanical DDR1 activation may be therapeutic.
No takes yet. Share an insight, caveat, or question.
Zhou et al. (2026) studied Chronic kidney disease-related atherosclerosis. SMC-specific Ddr1 deletion and DDR1 dephosphorylation-targeting chimera (DEPTAC) was evaluated on Aortic THBS1 levels, vascular stiffening, and atherosclerotic burden. Vascular SMC-specific Ddr1 deletion and DEPTAC treatment reduced aortic THBS1, vascular stiffening, and atherosclerosis in CKD models, while human plasma THBS1 correlated with CKD and atherosclerosis.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: