Macrophages secrete a heparin-binding inhibitor of endothelial cell growth.

Macrophages may play an important role in the regulation of angiogenesis by secreting modulators of endothelial cells (EC) proliferation. To investigate this, human mononuclear cells were plated in culture, and the conditioned media of these cells were analyzed by heparin-Sepharose affinity chromatography. The fractions were tested for modulation of EC growth, as determined by endothelial cell number in proliferation assays. A single peak of EC growth-inhibitory activity was found to elute from heparin-Sepharose with 1.0 M NaCl. Secretion of this EC inhibitor persisted for many weeks in cell culture, at which point the cultures consisted of adherent macrophages only. This activity was therefore designated as macrophage-derived endothelial cell inhibitor (MD-ECI). Analysis using specific neutralizing antisera as well as comparative heparin affinity analysis showed that MD-ECI was distinct from the known EC inhibitors TGF-beta and TNF-alpha. MD-ECI inhibits basal EC growth as well as FGF-stimulated EC growth. Its effect on EC is dose-dependent, nontoxic, and reversible.