DOT1L promotes phenotypic transition of vascular smooth muscle cells following vascular injury in diabetes through activation of the FGFR4/PI3K/AKT/Jag/Notch signaling pathway.

Vascular smooth muscle cell (VSMC) phenotypic transition contributes to restenosis, impacting the long-term efficacy of percutaneous coronary intervention in diabetic patients. While DOT1L is known to regulate atherosclerosis, its role in diabetic VSMC phenotypic modulation remains unclear. Using insulin-stimulated rat thoracic aorta VSMCs and a diabetic rat carotid artery balloon injury model, we investigated VSMC proliferation, migration, and collagen synthesis. Histological and molecular analyses were performed to assess vascular remodeling and protein expression. Our findings revealed that 100 nmol/L insulin stimulation for 24 h or 28 days post-injury significantly increased DOT1L and H3K79me1 expression, correlating with VSMC phenotypic changes. DOT1L overexpression upregulated synthetic phenotype proteins in VSMCs and carotid arteries, with a 4.07-fold increase in H3K79me1 at the FGFR4 promoter region, activating the PI3K/AKT/Jag1/Notch1 pathway. These results demonstrate that DOT1L promotes intimal hyperplasia in diabetic vascular injury by mediating VSMC phenotypic switching through H3K79me1-mediated FGFR4 activation and subsequent PI3K/AKT/Jag1/Notch1 signaling.