When the Moment Is Right, Will You Be Ninjurin?

Sci. Signal.  08 Jul 2014:
Vol. 7, Issue 333, pp. ec185
DOI: 10.1126/scisignal.2005663

Penile erection occurs when sexual stimulation induces the production of nitric oxide (NO) by nerves and endothelium in the corpus cavernosum. NO activates guanylate cyclase in local smooth muscle to produce cyclic guanosine monophosphate (cGMP), which promotes relaxation of the cytoskeleton and vasodilation. Type 5 phosphodiesterase (PDE5) degrades cGMP, and inhibitors of PDE5, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra), are used to treat erectile dysfunction (ED). Patients with ED caused by peripheral neurovascular pathology, such as diabetics, have limited bioavailability of NO and, thus, respond poorly to PDE5 inhibitors. Yin et al. explored the possibility that the homophilic cell adhesion protein Ninjurin 1, which is associated with inflammation in neurodegenerative disease and vascular regression during embryonic development, plays a role in ED in mice with pharmacologically induced diabetes. Diabetic mice had increased amounts of Ninjurin 1 in the penis and decreased electrically induced erectile responses. Diabetic mice 2 weeks after a single penile injection of Ninjurin 1-function–blocking antibodies or diabetic mice with Ninjurin 1 knockout had normal erectile responses. Penises of diabetic mice, but not diabetic mice with penile injection of Ninjurin 1 antibodies or diabetic Ninjurin 1–knockout mice, had reduced endothelium, endothelial cell proliferation, neuronal markers, and neurotrophic factors, as well as increased reactive oxygen species, endothelial cell death, and numbers of infiltrating Ninjurin 1–positive macrophages. Penises of diabetic mice, but not diabetic mice with penile injection of Ninjurin 1 antibodies, also had decreased amounts of angiopoietin 1, an angiogenic protein ligand that binds to the receptor tyrosine kinase Tie2. Mouse cavernous endothelial cells, but not those in which Ninjurin 1 was knocked down, grown in high glucose had decreased amounts of angiopoietin 1. Overexpression of Ninjurin 1 in the endothelial cells grown in normal glucose resulted in decreased amounts of angiopoietin 1. Injection of diabetic mice with sTie2-Fc, which blocks Tie2 activation by angiopoietin 1, prevented Ninjurin 1 antibodies from normalizing the abundance of endothelial and neuronal markers, neurotrophic factors, and reactive oxygen species and from improving erectile function in diabetic mice. Thus, Ninjurin 1 may inhibit neurovascular regeneration that contributes to ED in diabetes.

G. N. Yin, M. J. Choi, W. J. Kim, M.-H. Kwon, K.-M. Song, J.-M. Park, N. D. Das, K.-D. Kwon, D. Batbold, G. T. Oh, G. Y. Koh, K.-W. Kim, J.-K. Ryu, J.-K. Suh, Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse. Proc. Natl. Acad. Sci. U.S.A. 111, E2731–E2740 (2014). [Abstract] [Full Text]