Mouse model of erectile dysfunction due to diet-induced diabetes mellitus

Abstract

Objectives: To determine whether diet-induced diabetes mellitus (DM) in mice would reproduce the major features of human erectile dysfunction (ED) because DM is a significant risk factor in the development of ED.

Methods: In total, 150 C57BL6 (bl6) mice were divided into six groups of 25 mice each. Of these 150 mice, 125 were fed a high-fat (45% of total calories) diet for the final 4 (group 2), 8 (group 3), 12 (group 4), 16 (group 5), or 22 (group 6) weeks. Group 1 was fed a normal diet. The mice were 22 to 25 weeks old at study termination. The corporal tissues were harvested and studied for endothelium-dependent and endothelium-independent vasoreactivity, endothelial and smooth muscle cell content by immunohistochemistry, nitric oxide synthase expression by nicotinamide adenine dinucleotide-diaphorase staining, and apoptosis by terminal deoxynucleotidyl transferase biotin-D-UTP nick-end labeling staining.

Results: The blood glucose levels were greater in groups 2 to 6 compared with those in group 1. The vasoreactivity, endothelial cell content, and smooth muscle/collagen ratio were lower and apoptosis were greater in the DM mice (P = 0.0001, P = 0.10, P = 0.0002, P <0.001, and P <0.001, respectively). Significantly decreased nitric oxide synthase expression and significantly increased apoptosis (P <0.0001 each) was found in the high-fat diet mice.

Conclusions: Corporal tissue from mice with diet-induced DM demonstrated many of the major functional, structural, and biochemical changes found in humans with ED. This model should serve as a valuable tool for advancing our understanding of the role DM plays in the pathogenesis of ED.

Figure 1

Graph and table demonstrate the results of fasting and post glucose infusion (P.G.I.) serum glucose values from mice. Values were significantly higher in Groups 2, 3, 4, 5 and 6 vs. Group 1. The response to intra-peritoneal glucose is shown both graphically and in tabular form. HF = high fat.

Figure 2

The results of the vasoreactivity studies are shown for endothelium-dependent (A) and endothelium-independent vasoreactivity (B). In A, the response of pre-contracted corpus cavernosum to acetylcholine shown as the -Log[ED₅₀] are shown and these revealed that the endothelium-dependent vasoreactivity in the hyperglycemic mice was gradually lower in high fat diet groups (Group 1 vs. Group 4 or Group 5 or Group 6,* p<0.05 each). In B, the response to sodium nitroprusside is shown as the -Log[ED₅₀] and this value was gradually lower in high fat diet groups (Group 1 vs. Group 5 or Group 6, * p<0.05). HF = high fat.

Figure 2

The results of the vasoreactivity studies are shown for endothelium-dependent (A) and endothelium-independent vasoreactivity (B). In A, the response of pre-contracted corpus cavernosum to acetylcholine shown as the -Log[ED₅₀] are shown and these revealed that the endothelium-dependent vasoreactivity in the hyperglycemic mice was gradually lower in high fat diet groups (Group 1 vs. Group 4 or Group 5 or Group 6,* p<0.05 each). In B, the response to sodium nitroprusside is shown as the -Log[ED₅₀] and this value was gradually lower in high fat diet groups (Group 1 vs. Group 5 or Group 6, * p<0.05). HF = high fat.

Figure 3

Representative immunohistochemical stains of penile tissue form normal Diet (Group 1) and a mouse fed a high fat diet for 22 weeks (Group 6) showing endothelial cell (CD31, A and B, C, red), smooth muscle/ collagen ratio (Masson staining. D, E, F. Smooth muscle, pink; Collagen, blue), NOS expression (NADPH-diaphorase, G, H and I, blue), and apoptosis (TUNEL, J, K and L, brown). Photos for Masson staining were taken at 50x magnification while all other photos were taken at 200x magnification. Note the decreased endothelial cell content, smooth muscle/collagen ratio, NOS expression and an increase in apoptosis that occurs with diet induced diabetes. HF = high fat and NC = negative control.