Heparin-binding epidermal growth factor–like growth factor improves erectile function in streptozotocin-induced diabetic mice
Authors: Fridayana Fitri Rahma , Ock Jiyeon , Liu Fang-Yuan , Niloofar Lashkari , Vo Minh Nhat , Huang Yan , Yin Guo Nan , Ryu Ji-Kan 
Published: July 2024

Abstract

Background
Heparin-binding epidermal growth factor–like growth factor (HB-EGF) serves as a pro-angiogenic factor; however, there is to our knowledge currently no reported research on the relationship between HB-EGF and diabetic erectile dysfunction (ED).

Aim
In this study we aimed to determine whether HB-EGF can improve the erectile function of streptozotocin-induced diabetic mice and to explore the related mechanisms.

Methods
Eight-week-old male C57BL/6 mice were used for diabetes induction. Diabetes mellitus (DM) was induced by low-dose injections of streptozotocin (50 mg/kg) for 5 consecutive days. Eight weeks after streptozotocin injections, DM was determined by measuring blood glucose and body weight. Diabetic mice were treated with two intracavernous administrations of phosphate-buffered saline (20 μL) or various doses of HB-EGF (days −3 and 0; 1, 5, and 10 μg in 20 μL of phosphate-buffered saline). The angiogenesis effect of HB-EGF was confirmed by tube formation and migration assays in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was measured by electrical stimulation of the cavernous nerve, as well as histological examination and Western blot analysis for mechanism assessment.

Outcomes
In vitro angiogenesis, cell proliferation, in vivo intracavernous pressure, neurovascular regeneration, cavernous permeability, and survival signaling were the outcomes measured.

Results
Expression of HB-EGF was reduced under diabetic conditions. Exogenous HB-EGF induced angiogenesis in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was decreased in the DM group, whereas administration of HB-EGF resulted in a significant improvement of erectile function (91% of the age-matched control group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal cells. Histological and Western blot analyses revealed a significant increase in the permeability of the corpus cavernosum in DM mice, which was attenuated by HB-EGF treatment. The protein expression of phospho-Akt Ser473 and phosphorylated endothelial nitric oxide synthase Ser1177 increased after HB-EGF treatment.

Clinical Implications
The use of HB-EGF may be an effective strategy to treat ED associated with DM or other neurovascular diseases.

Strengths and Limitations
Similarly to other pro-angiogenic factors, HB-EGF has dual roles in vascular and neuronal development. Our study focused on broadly evaluating the role of HB-EGF in diabetic ED. In view of the properties of HB-EGF as an angiogenic factor, its dose concentration should be strictly controlled to avoid potential side effects.

Conclusion
In the diabetic ED mouse model in this study erectile function was improved by HB-EGF, which may provide new treatment strategies for patients with ED who do not respond to phosphodiesterase 5 Inhibitors.