© 1997 American Heart Association, Inc.
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Inhibitory Effects of Hypercholesterolemia and Ox-LDL on Angiogenesis-like Endothelial Growth in Rabbit Aortic Explants
Essential Role of Basic Fibroblast Growth Factor
From the Departments of Medicine (C.-H.C., Z.L., S.L., H.H.N., A.M.G. Jr, P.D.H.) and Pathology (J.C. Jr), Baylor College of Medicine, Houston, Tex.
Correspondence to Chu-Huang Chen, MD, PhD, Department of Medicine, Mail Station A601, Baylor College of Medicine, 6565 Fannin, Houston, TX 77030. E-mail cchen{at}bcm.tmc.edu
Abstract Hypercholesterolemic (HC) rabbits exhibit suppressed compensatory vascular growth after restriction of arterial supply. However, neovascularization is commonly found in atheromas containing inflammatory cells. We used an in vitro model to determine the effects of hypercholesterolemia on angiogenesis in the absence or presence of inflammatory cells. HC rabbit aortic explants (1 mm2) with or without (n=90 each) lesion-forming inflammatory cells were cultured in a collagen matrix with serum-free medium. Explant-derived endothelial cell growth was organized into capillary-like microtubes (CLM) that could be videomicroscopically quantified. CLM growth from lesion-free HC explants was significantly reduced to 13±4% of the value in explants (n=90) from normocholesterolemic (NC, n=15) rabbits (P<.001). In contrast, in lesion-containing HC explants, the matrix was invaded by foam cells, and CLM growth was not inhibited. Immunoassayable basic fibroblast growth factor (bFGF, in pg/mL) in the culture medium was significantly lower in lesion-free HC (<5) than NC explants (11±2, P<.01) or HC explants with lesions (14±3). In addition, CLM growth was reduced in NC explants incubated with oxidized LDL (ox-LDL, 50-100 µg/mL). Exogenous bFGF (10 ng/mL) reversed the inhibitory effects of hypercholesterolemia and ox-LDL, whereas bFGF-neutralizing antibody (10 µg/mL) abolished CLM growth in all groups. In cultured rabbit aortic endothelial cells, ox-LDL reduced DNA synthesis, but this inhibition was reversed by bFGF. We conclude that hypercholesterolemia and ox-LDL inhibit angiogenesis-like endothelial growth because of a suppressed availability of endogenous bFGF. Retained responsiveness to exogenous bFGF suggests that inducing bFGF expression at targeted sites may improve collateral growth in hyperlipidemic arterial disease.
Key Words: angiogenesis • hypercholesterolemia • oxidized LDL • basic fibroblast growth factor
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