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J. Biol. Chem., Vol. 276, Issue 11, 8135-8141, March 16, 2001
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From the The process of angiogenesis is important in both
normal and pathologic physiology. However, the mechanisms whereby
factors such as basic fibroblast growth factor promote the
formation of new blood vessels are not known. In the present study, we
demonstrate that exogenously added plasminogen activator inhibitor-1
(PAI-1) at therapeutic concentrations is a potent inhibitor of basic
fibroblast growth factor-induced angiogenesis in the chicken
chorioallantoic membrane. By using specific PAI-1 mutants with either
their vitronectin binding or proteinase inhibitor activities ablated,
we show that the inhibition of angiogenesis appears to occur via two
distinct but apparently overlapping pathways. The first is dependent on PAI-1 inhibition of proteinase activity, most likely chicken plasmin, while the second is independent of PAI-1's anti-proteinase activity and instead appears to act through PAI-1 binding to vitronectin. Together, these data suggest that PAI-1 may be an important factor regulating angiogenesis in vivo.
Inhibition of Angiogenesis in Vivo by Plasminogen
Activator Inhibitor-1*
,
,,
Department of Vascular Biology, J. H. Holland Laboratory, American Red Cross, Rockville, Maryland 20855 and
the § Department of Molecular Biology, Norris Cancer Center,
Topping Tower, University of Southern California,
Los Angeles, California 90033
*
This work was supported by National Institutes of Health
Grants HL55374, HL55747, and CA83090 (to D. A. L.) and CA74132 (to P. C. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept. of Medicine, Division of
Hematology-Oncology, University of Pittsburgh Cancer Institute, 200 Lothrop St. Pittsburgh, PA 15237.
**
Present address: Depts. of Radiation Oncology and Cell Biology, New
York University School of Medicine, The Kaplan Cancer Center/Rusk
Bldg., Rm. 812, 400 E. 34th St., New York, NY 10016.
To whom correspondence should be addressed: Dept. of Vascular
Biology, J. H. Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Tel.: 301-517-0356; Fax: 301-738-0794; E-mail: Lawrenced@usa.redcross.org.
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