Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesis.

Abstract

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.

• Authors: Lacramioara Ivanciu, Robert D Gerard, Haiwang Tang, Florea Lupu, Cristina Lupu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 27 Issue 2 Pg. 310-6 (Feb 2007) ISSN: 1524-4636 [Electronic] United States
• PMID: 17138934 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Glycoproteins
• RNA, Messenger
• tissue-factor-pathway inhibitor 2

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis (physiology)
• COS Cells
• Cell Line
• Cell Movement (physiology)
• Cells, Cultured
• Chlorocebus aethiops
• Endothelium, Vascular (cytology, physiology)
• Glycoproteins (genetics, physiology)
• Humans
• Mice
• Mice, Inbred C57BL
• Neovascularization, Physiologic (physiology)
• RNA, Messenger (genetics, physiology)
• Transduction, Genetic
• Up-Regulation (genetics, physiology)