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Macrophages secrete a heparin-binding inhibitor of endothelial cell growth
1Department of Surgery, Childrens Hospital, Boston, Massachusetts 02115.
Abstract:
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.
Insights
Macrophages secrete a novel inhibitor that regulates endothelial cell (EC) proliferation and angiogenesis. This macrophage-derived endothelial cell inhibitor (MD-ECI) affects basal and FGF-stimulated EC growth.
Area of Science:
- Cell Biology
- Immunology
- Angiogenesis Research
Background:
- Macrophages are implicated in regulating angiogenesis via secreted factors.
- Endothelial cell (EC) proliferation is a key component of angiogenesis.
Purpose of the Study:
- To investigate the role of macrophages in regulating EC proliferation.
- To identify and characterize novel mediators of EC growth secreted by macrophages.
Main Methods:
- Human mononuclear cells were cultured, and conditioned media analyzed.
- Heparin-Sepharose affinity chromatography was used to isolate active fractions.
- Endothelial cell proliferation assays determined growth modulation.
Main Results:
- A novel EC growth-inhibitory activity, macrophage-derived endothelial cell inhibitor (MD-ECI), was identified.
- MD-ECI elutes at 1.0 M NaCl from heparin-Sepharose and is secreted by macrophages.
- MD-ECI is distinct from TGF-beta and TNF-alpha, inhibiting both basal and FGF-stimulated EC growth in a dose-dependent, non-toxic, and reversible manner.
Conclusions:
- Macrophages secrete MD-ECI, a potent regulator of endothelial cell proliferation.
- MD-ECI represents a new factor involved in the complex process of angiogenesis.
- Further research into MD-ECI may reveal therapeutic targets for angiogenesis-related diseases.