Cholesterol feeding reduces vascular endothelial growth factor signaling in rabbit corporal tissues

Hypercholesterolemia is a major risk factor for erectile dysfunction (ED), but the mechanisms are not completely understood. Vascular endothelial growth factor (VEGF) is reduced in rabbit corporal tissue with cholesterol feeding. VEGF signaling leads to the phosphorylation of Akt and endothelial nitric oxide synthase (p-Akt and p-eNOS).

New Zealand White rabbits (n = 50) were fed a 1% cholesterol (n = 8, 8, 8, 4) or normal (n = 6, 6, 6, 4) diet for 2, 4.5, 7.5, and 12 weeks. Akt, p-Akt, and p-Akt/Akt were measured by enzyme-linked immunosorbent assay. Levels of eNOS, p-eNOS, and neuronal and inducible nitric oxide synthase (nNOS and iNOS) mRNA and protein were assessed by polymerase chain reaction and Western analysis.

Cholesterol feeding was associated with a significant decrease in p-Akt/Akt 2.16-fold (P < 0.05), 3.28-fold (P < 0.02), and 3.42-fold (P < 0.02) at 4.5, 7.5, and 12 weeks, respectively. The reduction in p-Akt/Akt with the cholesterol diet at 2 weeks was not significantly different, but the correlation between the duration of cholesterol feeding and the reduction in p-Akt/Akt was high (r( 2) = 0.858). eNOS protein or mRNA did not change with cholesterol feeding, but p-eNOS was significantly decreased at 4.5 weeks and all subsequent time points. nNOS mRNA and protein levels were decreased at 4.5 weeks and all subsequent time points, while iNOS was not different between groups.

Hypercholesterolemia results in decreased VEGF signaling and decreased levels of the active form of eNOS in corporal tissue. Levels of nNOS were reduced by a different mechanism. VEGF signaling may provide a target to modulate ED.