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on November 30, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print November 30, 2006, doi: 10.1161/01.ATV.0000254147.89321.cf
A more recent version of this article appeared on February 1, 2007
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Submitted on June 20, 2006
Accepted on November 15, 2006

Adenovirus-Mediated Expression of Tissue Factor Pathway Inhibitor-2 Inhibits Endothelial Cell Migration and Angiogenesis

Lacramioara Ivanciu ; Robert D. Gerard ; Haiwang Tang ; Florea Lupu ; and Cristina Lupu *

From the Cardiovascular Biology Research Program (L.I., H.T., F.L., C.L.), Oklahoma Medical Research Foundation, Oklahoma City; the Department of Internal Medicine (R.D.G.), University of Texas Southwestern Medical Center, Dallas; and the Department of Pathology (F.L.), Oklahoma University Health Sciences Center, Oklahoma City.

* To whom correspondence should be addressed. E-mail: cristina-lupu{at}omrf.ouhsc.edu.

Objective--Extracellular matrix (ECM) remodeling during angiogenesis is accomplished through plasmin-dependent pericellular proteolysis and through the action of matrix metalloproteinases (MMPs). Because tissue factor pathway inhibitor-2 (TFPI-2), a Kunitz-type protease inhibitor with prominent ECM localization, inhibits plasmin and MMPs activity, we investigated the role of TFPI-2 in endothelial cell (EC) migration and angiogenesis.

Methods and Results--Real-time polymerase chain reaction and immunostaining showed that the expression of TFPI-2 mRNA and protein was upregulated in migrating ECs. The effect of TFPI-2 on angiogenesis was studied in mouse models of Matrigel and polyvinylalcohol sponge implants by overexpressing TFPI-2 through infection with a replication-deficient adenovirus (AdTFPI-2). Using (immuno)fluorescence and confocal microscopy we observed that TFPI-2 reduced neovascularization and promoted ECM deposition. Lateral cell migration and capillary tube formation in vitro also were impaired by TFPI-2, a process reversed by anti-TFPI-2 antibodies. Increased apoptosis occurred both in AdTFPI-2-treated ECs and in the mouse implants. Zymography and assays in the absence of plasminogen confirmed plasmin inhibition as a main mechanism through which TFPI-2 inhibits EC migration.

Conclusions--Our data suggest that TFPI-2 may be an important regulator of aberrant angiogenesis associated with tumor growth/metastasis, cardiovascular diseases, chronic inflammation, or diabetes.
Key words: TFPI-2 • angiogenesis • endothelial cell • adenovirus gene delivery • mouse model






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