ATHEROSCLEROSIS AS A MICROVASCULAR DISEASE - IMPAIRED ANGIOGENESIS MEDIATED BY SUPPRESSED BASIC FIBROBLAST GROWTH-FACTOR EXPRESSION

We present evidence that hypercholesterolemia and oxidized low-density lipoprotein (ox-LDL) impair endothelial cell growth by suppressing ba sic fibroblast growth factor (bFGF) expression. Background studies sho w that diet-induced hypercholesterolemia in rabbits impairs hyperplast ic lumen-expanding remodeling of the carotid artery in response to a c hronic flow load. Hypercholesterolemia also markedly impairs compensat ory macrovascular and microvascular growth in rabbit ears with surgica l restriction of arterial supply. In an in vitro model of angiogenesis , arterial explants cultured in a three-dimensional collagen gel exhib ited organized endothelial cell growth with formation of capillary-lik e microtubes (CLM). CLM growth was sensitive to inhibition by neutrali zing antibodies against bFGF. With explants excised from both the aort a of hypercholesterolemic rabbits and from coronary arteries of patien ts with coronary arteriosclerosis, CLM growth and release of immunoass ayable bFGF to the culture medium were suppressed. Growth suppression was reversed partially by exogenous bFGF. In control explants, ox-LDL produced a suppression of CLM growth that could be reversed by exogeno us bFGF. In endothelial cells in culture, ox-LDL suppressed bFGF expre ssion and DNA synthesis in a dose-dependent manner. We conclude that a therosclerosis is associated with impaired bFGF-dependent endothelial cell growth manifested by impaired adaptive growth responses of large arteries and microvessels.