Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db/db mouse.
BACKGROUND
Patients with erectile dysfunction (ED) associated with type II diabetes often have impaired endothelial function and tend to respond poorly to oral phosphodiesterase type 5 inhibitors. Therefore, neovascularization is a promising strategy for curing diabetic ED.


OBJECTIVE
To determine the effectiveness of a soluble, stable, and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, in promoting cavernous angiogenesis and erectile function in a mouse model of type II diabetic ED. Methods.  Sixteen-week-old male db/db mice (in which obesity and type II diabetes are caused by a mutation in the leptin receptor) and control C57BL/6J mice were used and divided into four groups (N=14 per group): age-matched controls; db/db mice receiving two successive intracavernous injections of phosphate-buffered saline (PBS) (days -3 and 0; 20 µL); db/db mice receiving a single intracavernous injection of COMP-Ang1 protein (day 0; 5.8 µg/20 µL); and db/db mice receiving two successive intracavernous injections of COMP-Ang1 protein (days -3 and 0; 5.8 µg/20 µL).


METHODS
Two weeks later, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was then harvested and stained with antibodies to platelet/endothelial cell adhesion molecule-1 (PECAM-1) (endothelial cell marker), phosphohistone H3 (PH3, a nuclear protein indicative of cell proliferation), phospho-endothelial nitric oxide synthase (eNOS), and eNOS. Penis specimens from a separate group of animals were used for cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) quantification.


RESULTS
Local delivery of COMP-Ang1 protein significantly increased eNOS phosphorylation and cGMP and cAMP expression compared with that in the group treated with PBS. Repeated intracavernous injections of COMP-Ang1 protein completely restored erectile function and cavernous endothelial content through enhanced cavernous neoangiogenesis as evaluated by PECAM-1 and PH3 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay, whereas a single injection of COMP-Ang1 protein elicited partial improvement.


CONCLUSIONS
Cavernous neovascularization using recombinant Ang1 protein is a novel therapeutic strategy for the treatment of ED resulting from type II diabetes.
Jin
Hai-Rong
HR
National Research Laboratory of Regenerative Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
Kim
Woo Jean
WJ
Song
Jae Sook
JS
Piao
Shuguang
S
Tumurbaatar
Munkhbayar
M
Shin
Sun Hwa
SH
Choi
Min Ji
MJ
Tuvshintur
Buyankhuu
B
Song
Kang-Moon
KM
Kwon
Mi-Hye
MH
Yin
Guo Nan
GN
Koh
Gou Young
GY
Ryu
Ji-Kan
JK
Suh
Jun-Kyu
JK
D042683:Angiopoietin-1 / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000242:Cyclic AMP; D006152:Cyclic GMP; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects*; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D042683:Angiopoietin-1; D058986:Phosphodiesterase 5 Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; D000242:Cyclic AMP; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP