INHIBITORY EFFECTS OF HYPERCHOLESTEROLEMIA AND OX-LDL ON ANGIOGENESIS-LIKE ENDOTHELIAL GROWTH IN RABBIT AORTIC EXPLANTS - ESSENTIAL ROLE OFBASIC FIBROBLAST GROWTH-FACTOR

Hypercholesterolemic (HC) rabbits exhibit suppressed compensatory vasc ular growth after restriction of arterial supply. However, neovascular ization is commonly found in atheromas containing inflammatory cells. We used an in vitro model to determine the effects of hypercholesterol emia on angiogenesis in the absence or presence of inflammatory cells. HC rabbit aortic explants (1 mm(2)) with or without (n=90 each) lesio n-forming inflammatory cells were cultured in a collagen matrix with s erum-free medium. Explant-derived endothelial cell growth was organize d into capillary-like microtubes (CLM) that could be videomicroscopica lly quantified. CLM growth from lesion-free HC explants was significan tly reduced to 13+/-4% of the value in explants (n=90) from normochole sterolemic (NC, n=15) rabbits (P<.001). In contrast, in lesion-contain ing HC explants, the matrix was invaded by foam cells, and CLM growth was not inhibited. Immunoassayable basic fibroblast growth factor (bFG F, in pg/mL) in the culture medium was significantly lower in lesion-f ree HC (<5) than NC explants (11+/-2, P<.01) or HC explants with lesio ns (14+/-3). In addition, CLM growth was reduced in NC explants incuba ted with oxidized LDL (ox-LDL, 50-100 mu g/mL). Exogenous bFGF (10 ng/ mL) reversed the inhibitory effects of hypercholesterolemia and ox-LDL , whereas bFGF-neutralizing antibody (10 pg/mL) abolished CLM growth i n all groups. In cultured rabbit aortic endothelial cells, ox-LDL redu ced DNA synthesis, but this inhibition was reversed by bFGF. We conclu de that hypercholesterolemia and ox-LDL inhibit angiogenesis-like endo thelial growth because of a suppressed availability of endogenous bFGF . Retained responsiveness to exogenous bFGF suggests that inducing bFG F expression at targeted sites may improve collateral growth fn hyperl ipidemic arterial disease.