Targeting SETD7 Rescues Diabetes-Induced Impairment of Angiogenic Response by Transcriptional Repression of Semaphorin-3G

Hyperglycemia increases SETD7 expression and SETD7-dependent histone 3 on lysine 4, thus leading to an open chromatin and active transcription of the antiangiogenic gene semaphorin-3G (SEMA3G). Gene silencing and selective pharmacological inhibition of SETD7 by (R)-PFI-2 both blunt histone 3 on lysine 4 levels and SEMA3G transcription, thus rescuing hyperglycemia-induced impairment of angiogenic properties. The SETD7 inhibitor (R)-PFI-2 promotes neovascularization and restores limb perfusion in diabetic mice. SETD7/SEMA3G signaling was dysregulated in two different cohorts of patients with diabetes with peripheral arterial disease. Treatment with (R)-PFI-2 in endothelial cells collected from patients with diabetes restores angiogenic properties.