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Atherosclerosis is a significant risk factor for cardiovascular diseases, mainly driven by abnormal mechanical transduction in vascular smooth muscle cells (VSMCs). However, the key mechanical sensors and their underlying mechanisms remain elusive. Through a 5/6 nephrectomy mouse model, we identified that the kidney disease receptor A2 (EphA2) was significantly upregulated in hardened arteries. Genetic deletion of Epha2 in VSMCs significantly reduced arterial sclerosis. Using different stiffness polyacrylamide gels and in situ rod bio-click hydrogels, we demonstrated that matrix reinforcement directly induced EphA2 phase separation, forming biomolecular condensates that recruited and activated ERK1/2 as a signaling hub. This led to phosphorylation of the transcription factor CREB, subsequently promoting the upregulation of the restructured nuclear receptor NR4A3. To translate this finding, we designed an inverse peptide that targeted the intrinsic disorder region (IDR) of EphA2, effectively disrupting phase separation and alleviating the functional impairment of VSMCs in vitro. Crucially, delivery of this peptide via VAPG-modified nanoparticles in vivo significantly alleviated mouse arterial calcification and sclerosis. Our study established EphA2 phase separation as a key mechanism in vascular mechanical transduction and revealed a new EphA2-ERK1/2-NR4A3 signaling axis, thereby proposing a promising therapeutic strategy that targets pathological biomolecular condensates to combat atherosclerosis. This study was published in the journal Bioactive Materials under the title "Targeting mechanosensitive EphA2 phase separation to alleviate arterial stiffening".
Reference News:
DOI: 10.1016/j.bioactmat.2026.01.020
