title: Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Accumulating evidence suggests that exaggerated formation of vasa vasorum (VV) plays an important role in the pathogenesis of atherosclerosis. However, it remains unclear whether augmented angiogenesis in the adventitia could promote hyperlipidemia-induced atherosclerotic lesion formation.
  
  
  RESULTS
  First, we analyzed the time course of VV development in apolipoprotein E-deficient (ApoE-/-) mice. VV proliferation was observed only after atherosclerotic lesion formation. Next, we investigated whether forced perivascular angiogenesis could promote plaque progression. Basic fibroblast growth factor (bFGF) (100 μg/body) incorporated in acid gelatin hydrogel microspheres (AGHM) (bFGF+AGHM group, n=10), AGHM alone (AGHM group, n=7), or PBS (control group, n=8) was administered into the periaortic area of the retroperitoneal space in 10- to 11-week-old male ApoE-/- mice. At 13 weeks after the operation, lesions were significantly larger in the bFGF+AGHM group than in others (bFGF+AGHM: 3.4 ± 0.7 × 10(4)μm(2); AGHM: 0.1 ± 0.1 × 10(4)μm(2); control: 0 μm(2); p<0.0001), which was associated with increased neovascularization in the adventitia. The number of adventitial capillaries correlated with plaque size (r=0.69, p<0.0001). In the bFGF+AGHM group, an increase in the number of VV and accumulation of Mac3-positive macrophages were observed prior to atherosclerotic lesion formation.
  
  
  CONCLUSIONS
  Our findings demonstrated that local administration of bFGF in the adventitia induced development of VV and accelerated plaque progression in ApoE-/- mice, supporting the notion that VV formation plays a crucial role in the pathogenesis of atherosclerosis.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Tanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000473:pathology; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D016222:Fibroblast Growth Factor 2; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D014651:Vasa Vasorum / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E; D016222:Fibroblast Growth Factor 2