Extracellular matrix-derived angiogenic factor(s) inhibit endothelial cell proliferation, enhance differentiation, and stimulate angiogenesis in vivo.
To isolate matrix molecules with angiogenic activity, tumor extracellular matrix (ECM) fractions from the basement membrane preparation Matrigel were analyzed for effects on endothelial cell (EC) proliferation, differentiation, and vessel formation in vivo. Inhibition of human and bovine EC DNA synthesis was evident upon treatment with several soluble Matrigel fractions including conditioned media (MGCM). After size fractionation of MGCM, EC growth arrest was activated by factor(s) smaller than 3,000 daltons (3KF). Bovine EC differentiation (tube formation) was promoted by both MGCM and 3KF fractions in two different models using matrigel or collagen gels to stimulate tube formation. The 3KF factor(s) stimulated angiogenesis when implanted in the cornea or subcutaneously in mice. FGF-induced angiogenesis and blood flow were increased in the presence of 3KF factor(s), an effect that was inhibited by the anti-angiogenic molecule endostatin. Further characterization of the low molecular weight 3KF samples by RP-HPLC revealed several fractions exhibiting EC growth arrest activity. These results suggest that the ability of ECM preparations to induce EC growth arrest and tube formation may reside, at least partially, in previously undetected low molecular weight molecules. Characterization of these ECM-associated inhibitors may lead to the development of novel anti-angiogenic and anti-tumor compounds.
Akhta
N
N
The Department of Pathology, University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore 21201, USA. apass001@umaryland.edu
Carlso
S
S
Pesarini
A
A
Ambulos
N
N
Passaniti
A
A
D043925:Angiogenesis Inducing Agents / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D014471:Umbilical Veins / Q000166:cytology; D014947:Wounds and Injuries / Q000188:drug therapy
D043925:Angiogenesis Inducing Agents; D017077:Culture Media, Conditioned; D006133:Growth Substances