title: Chronic endothelin receptor antagonism prevents coronary vasa vasorum neovascularization in experimental hypercholesterolemia.
abstract: OBJECTIVE
  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 mm(2) vs. 2.5 +/- 1.5 per mm(2); p < 0.05) and was preserved in the HC + ET-A group (3.2 +/- 0.7 per mm(2)). 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.
authors: Division of Cardiovascular Diseases, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA.
authors: Joerg
authors: J
authors: Herrmann
authors: Patricia J
authors: PJ
authors: Best
authors: Erik L
authors: EL
authors: Ritman
authors: David R
authors: DR
authors: Holmes
authors: Lilach O
authors: LO
authors: Lerman
authors: Amir
authors: A
authors: Lerman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003324:Coronary Artery Disease / Q000378:metabolism*; D003331:Coronary Vessels / Q000473:pathology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000032:analysis*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006937:Hypercholesterolemia / Q000378:metabolism*; D007150:Immunohistochemistry; D008222:Lymphokines / Q000032:analysis*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D013552:Swine; D014057:Tomography, X-Ray Computed / Q000379:methods; D014651:Vasa Vasorum / Q000000981:diagnostic imaging / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D002791:Cholesterol, Dietary; D016228:Endothelial Growth Factors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors