Published online before print August 23, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070074

Accepted for publication June 25, 2007.

Article

Tumoral and Choroidal Vascularization. Differential Cellular Mechanisms Involving Plasminogen Activator Inhibitor Type I

Maud Jost^*, Catherine Maillard^*, Julie Lecomte^*, Vincent Lambert^*, Marc Tjwa, Pierre Blaise, Maria-Luz Alvarez Gonzalez^*, Khalid Bajou^*, Silvia Blacher^*, Patrick Motte, Chantal Humblet^¶, Marie Paule Defresne^¶, Marc Thiry^||, Francis Frankenne^*, André Gothot^**, Peter Carmeliet, Jean-Marie Rakic, Jean-Michel Foidart^*, and Agnès Noël^*@

From the Laboratories of Tumor and Development Biology,* and Histology,^¶ Centre de Recherche en Cancérologie Expérimentale (CRCE), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R), Center for Biomedical Integrative Genoproteomics, the Department of Life Sciences, Laboratory of Plant Cell Biology, the Laboratories of Cell and Tissue Biology^|| and Hematology,** and the Departments of Ophthalmology and Gynecology, Centre Hospitalier Universitaire, University of Liège, Liège; and the Center for Transgene Technology and Gene Therapy, Katholieke Universiteit Leuven, Leuven, Belgium

^@ To whom correspondence should be addressed. E-mail: agnes.noel{at}ulg.ac.be.

	Abstract

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1^-/- mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1^-/- BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis.