Prevention of vasa vasorum neovascularization attenuates early neointima formation in experimental hypercholesterolemia.
Vasa vasorum (VV) neovascularization is a key feature of early atherosclerosis and adds substantial endothelial exchange-surface to the coronary vessel wall. Thus, it is conceivable that VV neovascularization favors the entry of pro-inflammatory and pro-atherosclerotic blood components into the coronary vessel wall. We sought to investigate the effects of Thalidomide (Th), a potent anti-angiogenic drug on vasa vasorum (VV) neovascularization, vessel wall inflammation, and neointima formation in early experimental atherosclerosis. Female domestic swine, 3 months old, were fed normal (N, n = 12) or high-cholesterol diet (HC, n = 12) for 3 months. In each group six pigs were randomized to 200 mg Thalidomide daily for the diet period (N + Th, HC + Th). LADs were scanned with micro-CT (20 microm cubic voxel size) to determine VV spatial density (#/mm2). Fresh-frozen coronary tissue was used for western blotting (VEGF, TNF-alpha, LOX-1, Ikappabetaalpha and Gro-alpha) and electrophoretic mobility shift assay (EMSA, NFkappabeta). Treatment with Thalidomide preserved VV spatial density [2.7 +/- 0.3 (N), 6.4 +/- 0.7 (HC), 3.5 +/- 0.8 (HC + Th); p = ns HC + Th vs. N] and inhibited the expression of VEGF, TNF-alpha and LOX-1, but not NFkappabeta activity in the coronary vessel wall. Immunofluorescence analyses revealed co-localization of vWF but not SMA and NFkappabeta, TNF-alpha as well as VEGF in HC and HC + Th coronaries. Intima-media thickness was significantly inhibited in HC + Th compared to HC. Serum levels of hs-CRP and TNF-alpha did not differ among the groups. Our study supports a role of VV neovascularization in the development of and a therapeutic potential for anti-angiogenic intervention in early atherosclerosis.
Gössl
Mario
M
Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA.
Herrmann
Jörg
J
Tang
Hui
H
Versari
Daniele
D
Galili
Offer
O
Mannheim
Dallit
D
Rajkumar
S Vincent
SV
Lerman
Lilach O
LO
Lerman
Amir
A
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D054360:Chemokine CXCL1 / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006937:Hypercholesterolemia / Q000473:pathology*; D051550:I-kappa B Kinase / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology*; D013552:Swine; D013792:Thalidomide / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014651:Vasa Vasorum / Q000187:drug effects / Q000473:pathology*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D000199:Actins; D020533:Angiogenesis Inhibitors; D054360:Chemokine CXCL1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D013792:Thalidomide; D051550:I-kappa B Kinase