<b>Targeting SETD7 Rescues Diabetes-induced Impairment of Angiogenic Response by Transcriptional Repression of Semaphorin 3G</b>

<p dir="ltr">Revascularization strategies failed to improve outcome in diabetic (DM) patients with peripheral artery disease (PAD). Histone modifications are key modulators of gene expression and could play a role in angiogenic response. This study investigates the role of chromatin remodelling in modulating angiogenesis in DM. RNA sequencing (RNA-seq) and angiogenic assays (cell migration and tube formation) were performed in human aortic endothelial cells (HAECs) exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48h. The expression of the histone methyltransferase SETD7 and its chromatin signature at histone 3 on lysine 4 (H3K4me1) were investigated by Western blot and chromatin immunoprecipitation (ChIP). Diabetic mice were treated with the SETD7 inhibitor <i>(R)</i>-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation. The experimental findings were translated into two cohorts of DM patients with PAD. RNA-seq in HG-treated HAECs unveiled SETD7 as the top-ranking transcript. SETD7 upregulation was associated with increased H3K4me1 levels and defective angiogenesis. Both SETD7 depletion and <i>(R)</i>PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7-induced H3K4me1 enables the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA3G) by increasing chromatin accessibility to PPARγ. In diabetic mice with hindlimb ischemia, (<i>R</i>)-PFI-2 improved limb perfusion by suppressing SEMA3G. SETD7/SEMA3G axis was upregulated in DM patients with PAD. Of note, (<i>R</i>)-PFI-2 restored angiogenic properties in endothelial cells collected from DM patients. These findings show that SETD7 is a druggable epigenetic target in diabetic PAD.</p>