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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

View larger version (114K): [in a new window]   Figure 1 Representative microcomputed tomography images of the proximal segments of the left anterior descending artery from animals fed a normal diet (N) (left panel) or high cholesterol diet without (HC) (middle panel) or with endothelin-type A-receptor antagonism (HC + ET-A) (right panel) for 12 weeks. The spatial distribution pattern of vasa vasorum in the N group is characterized by a clear structure into first order vasa vasorum, running longitudinally and second order vasa vasorum, running circumferentially. In the HC group, a plexus of newly formed vasa vasorum and in the HC + ET-A group a restitution to a normal status are apparent. Illustration voxel size 21 µm.

View larger version (106K): [in a new window]   Figure 2 Double-immunostaining for smooth muscle cell alpha-actin (red) and VEGF (brown) of histologic cross-sections of coronary arteries from animals fed a normal diet (N) (A and B) or high cholesterol diet without (HC) (C and D) or with endothelin-type-A receptor antagonism (HC + ET-A) (E and F) for 12 weeks. In contrast with the other two groups, intense vascular endothelial growth factor immunoreactivity is apparent in the outer media and adjacent adventitia in the HC group, including vasa vasorum (arrow in D). Original magnification for (A) 37.5x, for (B) 62.5x, for (C) 62.5x, for (D) 125x, for (E) 62.5x and for (F) 100x.

View larger version (20K): [in a new window]   Figure 3 Bar graph illustrating vascular endothelial growth factor expression in the coronary arterial wall from animals fed a normal diet (N, n = 4) or high cholesterol diet without (HC, n = 3) or with endothelin-type-A receptor antagonism (HC + ET-A, n = 3) for 12 weeks. Vascular endothelial growth factor protein content was higher in the HC group than in the N group (p = 0.06) and significantly lower in the HC + ET-A group than in the HC group. *p < 0.05. Values are mean ± standard error.