Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice

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. Methods and 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 mu g/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 +/- .7 x 104 mu m2; AGHM: 0.1 +/- 0.1 x 104 mu m2; control: 0 mu m2; 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 W and accelerated plaque progression in ApoE-/- mice, supporting the notion that W formation plays a crucial role in the pathogenesis of atherosclerosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.