Penile erection is a neurovascular phenomenon, and erectile dysfunction (ED) is caused mainly by vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances.Men with diabetic ED often have severe endothehal dysfunction and peripheral nerve damage,which result in poor response to oral phosphodiesterase-5 inhibitors.Nerve injury-induced protein 1 (Ninjurin 1,Ninj 1) is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period.Here, we demonstrate in streptozotocininduced diabetic mice that inhibition of the Ninj 1 pathway by administering Ninj 1-neutralizing antibody (Ninj 1-Ab)or by using Ninj 1-knockoutmice successfully restored erectile function through enhanced penile angiogenesis and neural regeneration.Angiopoietin-1 (Angl) expression was down-regulated and angiopoietin-2 expression was up-regulated in the diabetic penis compared with that in controls, and these changes were reversed by treatment with Ninj 1-Ab.Ninj 1 blockade-mediated penile angiogenesis and neural regeneration as well as recovery of erectile function were abolished by inhibition of Ang 1-Tie2 (tyrosine kinase with Ig and epidermal growth factor homology domain-2) signaling with soluble Tie2 antibody or Ang1 siRNA.The present results suggest that inhibition of the Ninj 1 pathway will be a novel therapeutic strategy for treating ED.