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Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2644-51. doi: 10.1161/ATVBAHA.112.252544. Epub 2012 Sep 13.

Fibroblast growth factor-2 is required for vasa vasorum plexus stability in hypercholesterolemic mice.

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Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
Contributed equally



Vasa vasorum are angiogenic in advanced stages of human atherosclerosis and hypercholesterolemic mouse models. Fibroblast growth factor-2 (FGF-2) is the predominant angiogenic growth factor in the adventitia and plaque of hypercholesterolemic low-density lipoprotein receptor-deficient/apolipoprotein B(100/100) mice (DKO). FGF-2 seems to play a role in the formation of a distinct vasa vasorum network. This study examined the vasa vasorum structure and its relationship to FGF-2.


DKO mice treated with saline, antiangiogenic recombinant plasminogen activator inhibitor-1(23) (rPAI-1(23)), or soluble FGF receptor 1 were perfused with fluorescein-labeled Lycopersicon esculentum lectin. Confocal images of FGF-2-probed descending aorta adventitia show that angiogenic vasa vasorum form a plexus-like network in saline-treated DKO similar to the FGF-2 pattern of distribution. Mice treated with rPAI-1(23) and soluble FGF receptor 1 lack a plexus; FGF-2 and vasa vasorum density and area are significantly reduced. A perlecan/FGF-2 complex is critical for plexus stability. Excess plasmin produced in rPAI-1(23)-treated DKO mice degrades perlecan and destabilizes the plexus. Plasmin activity and plaque size measured in DKO and DKO/plasminogen activator inhibitor-1(-)(/-) mice demonstrate that elevated plasmin activity contributes to reduced plaque size.


An FGF-2/perlecan complex is required for vasa vasorum plexus stability. Elevated plasmin activity plays a significant inhibitory role in vasa vasorum plexus and plaque development.

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