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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.

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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