Chronic endothelin receptor antagonism prevents. Coronary vasa vasorum neovascularization in experimental hypercholesterolemia

OBJECTIVES: The purpose of this study was to test the hypothesis that endothelin (ET) receptor antagonism reduces coronary vasa vasorum neovascularization in experimental hypercholesterolemia. BACKGROUND: Experimental hypercholesterolemia is associated with increased expression of ET-1, an endothelium-derived peptide with vasoconstricting, mitogenic and angiogenic properties, in the coronary arterial wall as well as with vasa vasorum neovascularization. A pathomechanistic role of the endogenous ET system in vasa vasorum neovascularization in hypercholesterolemia has, however, remained uncertain so far. METHODS: Female domestic pigs were placed on a normal diet (N; n = 7) or on a hypercholesterolemic diet without (HC; n = 6) or with ET-A receptor antagonism (ABT-627, 4 mg/kg/day; HC + ET-A; n = 6). After 12 weeks, coronary vasa vasorum structure was assessed by three-dimensional microscopic computed tomography, expression of vascular endothelial growth factor (VEGF) within the coronary arterial wall by Western blotting and immunostaining. RESULTS: Compared with the N group, plasma concentrations of low-density lipoprotein cholesterol were higher in both the HC and HC + ET-A groups (36 ± 3 mg/dl vs. 312 ± 153 mg/dl and 303 ± 113 mg/dl, p < 0.01). Vasa vasorum density was higher in the HC group compared with the N group (4.7 ± 1.8 per mm² vs. 2.5 ± 1.5 per mm²; p < 0.05) and was preserved in the HC + ET-A group (3.2 ± 0.7 per mm²). In parallel, increase in VEGF expression in the coronary arterial wall in the HC group was preserved in the HC + ET-A group. CONCLUSIONS: The current study demonstrates that chronic endothelin receptor antagonism prevents the increase in VEGF expression and vasa vasorum density of coronary arteries in experimental hypercholesterolemia. These findings support a role for the endogenous ET system in vasa vasorum neovascularization in early coronary atherosclerosis.