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 basic fibroblast growth factor (bFGF) expression. Background studies show that diet-induced hypercholesterolemia in rabbits impairs hyperplastic lumen-expanding remodeling of the carotid artery in response to a chronic flow load. Hypercholesterolemia also markedly impairs compensatory macrovascular and microvascular growth in rabbit ears with surgical restriction of arterial supply. In an in vitro model of angiogenesis, arterial explants cultured in a three-dimensional collagen gel exhibited organized endothelial cell growth with formation of capillary-like microtubes (CLM). CLM growth was sensitive to inhibition by neutralizing antibodies against bFGF. With explants excised from both the aorta of hypercholesterolemic rabbits and from coronary arteries of patients with coronary arteriosclerosis, CLM growth and release of immunoassayable 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 exogenous bFGF. In endothelial cells in culture, ox-LDL suppressed bFGF expression and DNA synthesis in a dose-dependent manner. We conclude that atherosclerosis is associated with impaired bFGF-dependent endothelial cell growth manifested by impaired adaptive growth responses of large arteries and microvessels.