EXPERIMENTAL STUDY
Chronic endothelin receptor antagonism prevents coronary vasa vasorum neovascularization in experimental hypercholesterolemia
Joerg Herrmann, MD*,
Patricia J. Best, MD*,
Erik L. Ritman, MD, PhD ,
David R. Holmes, Jr, MD, FACC*,
Lilach O. Lerman, MD, PhD and
Amir Lerman, MD, FACC*,*
* Division of Cardiovascular Diseases, Mayo Clinic Rochester, Rochester, Minnesota, USA
Department of Physiology and Biophysics, Mayo Clinic Rochester, Rochester, Minnesota, USA
Department of Hypertension, Division of Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota, USA
Manuscript received August 17, 2001;
revised manuscript received February 7, 2002,
accepted February 8, 2002.
* Reprint requests and correspondence: Dr. Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA. lerman.amir{at}mayo.edu
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.
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Abbreviations and Acronyms
| | Ang II | | angiotensin II | | DAB | | 3,3-diaminobenzidine tetra-hydrochloride | | ET-A | | endothelin-type-A | | ET-B | | endothelin-type-B | | ET-1 | | endothelin-1 | | HC | | high cholesterol diet | | HC + ET-A | | high cholesterol diet plus ET-A antagonist | | N | | normal diet | | RAS | | renin-angiotensin system | | VEGF | | vascular endothelial growth factor |
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