Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse.
BACKGROUND
Erectile dysfunction (ED) is a highly prevalent complication of diabetes, and the severity of endothelial dysfunction is one of the most important factors in reduced responsiveness to oral phosphodiesterase type 5 inhibitors.


OBJECTIVE
To study the effects of human angiopoietin-4 (Ang-4) protein on erectile function in diabetic mice.


METHODS
Diabetes was induced by intraperitoneal injection of streptozotocin into 8-week-old C57BL/6J male mice. At 8 weeks after the induction of diabetes, the animals were divided into four groups: control nondiabetic mice and diabetic mice receiving two successive intracavernous injections of phosphate buffered saline (days -3 and 0), a single intracavernous injection of Ang-4 protein (day 0), or two successive intracavernous injections of Ang-4 protein (days -3 and 0).


METHODS
One week after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested and stained with hydroethidine or antibodies to Ang-4, platelet/endothelial cell adhesion molecule-1, and phosphorylated endothelial nitric oxide synthase (eNOS). We also determined the differential expression of Ang-4 in cavernous tissue in the control and diabetic mice. The effect of Ang-4 protein on the phosphorylation of Tie-2, Akt, and eNOS was determined in human umbilical vein endothelial cells (HUVECs) by Western blot.


RESULTS
The cavernous expression of Ang-4 was downregulated in diabetic mice; Ang-4 was mainly expressed in endothelial cells. Local delivery of Ang-4 protein significantly increased cavernous endothelial content, induced eNOS phosphorylation, and decreased the generation of superoxide anion and apoptosis in diabetic mice. Ang-4 protein strongly increased the phosphorylation of Tie-2, Akt, and eNOS in HUVECs. Repeated intracavernous injections of Ang-4 induced significant restoration of erectile function in diabetic mice (87% of control values), whereas a single intracavernous injection of Ang-4 protein elicited modest improvement.


CONCLUSIONS
Cavernous endothelial regeneration by use of Ang-4 protein may have potential for the treatment of vascular disease-induced ED, such as diabetic ED.
National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
Mi-Hye
MH
Kwon
Ji-Kan
JK
Ryu
Woo Jean
WJ
Kim
Hai-Rong
HR
Jin
Kang-Moon
KM
Song
Ki-Dong
KD
Kwon
Dulguun
D
Batbold
Guo Nan
GN
Yin
Gou Young
GY
Koh
Jun-Kyu
JK
Suh
D042683:Angiopoietin-1 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D042682:Angiopoietins / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism / Q000502:physiology; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000098:blood supply / Q000187:drug effects*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects
D042683:Angiopoietin-1; D042682:Angiopoietins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C118117:angiopoietin 4; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
Angiogenesis; Angiopoietin-4; Diabetes Mellitus; Endothelial Dysfunction; Enhanced Responsiveness to PDE5 Inhibitors; Erectile Dysfunction; Therapeutic Protein