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Hemochorial Placentation in the Primate: Expression of Vascular Endothelial Growth Factor, Angiopoietins, and Their Receptors Throughout Pregnancy¹

^a Medical Research Council, Human Reproductive Sciences Unit, Edinburgh EH3 9ET, United Kingdom ^b Department of Obstetrics and Gynecology of the University of Ulm, 89075 Ulm, Germany ^c Regeneron Pharmaceuticals, Tarrytown, New York 10591

Vascular development and its transformation are necessary for successful hemochorial placentation, and vascular endothelial growth factor (VEGF), angiopoietins, and their receptors may be involved in the molecular regulation of this process. To determine the potential role of these putative regulators in a widely studied primate, the common marmoset, we investigated their mRNA expression and protein location in the placenta throughout pregnancy using in situ hybridization, Northern blot analysis, and immunocytochemistry. VEGF was localized in decidual and cytotrophoblast cells, and its highest expression was found in the maternal decidua. The Flt receptor was exclusively detected in the syncytial trophoblast with increasing expression in placentae from 10 wk to term. Soluble Flt (sFlt) was also detectable by Northern blot analysis. KDR receptor expression was restricted to mesenchymal cells during early placentation and to the fetoplacental vasculature during later placentation. KDR expression increased throughout pregnancy. Angiopoietin-1 (Ang-1) was localized in the syncytial trophoblast, being highly expressed in the second half of gestation. Ang-2 mRNA localized exclusively to maternal endothelial cells, and was highly expressed in 10-wk placentae. The Tie-2 receptor was found in cytotrophoblast cells and in fetal and maternal vessels. High Tie-2 levels were detected in the wall of chorion vessels at 14-wk, 17-wk, and term placentae. These results suggest that the processes of trophoblast invasion, maternal vascular transformation, and fetoplacental vascular differentiation and development are regulated by the specific actions of angiogenic ligand-receptor pairs. Specifically, 1) VEGF/Flt and Ang-1/Tie-2 may promote trophoblast growth, 2) VEGF/KDR and Ang-1/Tie-2 may support fetoplacental vascular development and stabilization, 3) sFlt may balance VEGF actions, and 4) Ang-2/Tie-2 may remodel the maternal vasculature.

First decision: 18 July 2001.

¹ This work was supported in part by a grant to C.W. from Deutsche Forschungsgemeinschaft.

² Correspondence and current address: C. Wulff, Department of Obstetrics and Gynecology of the University of Ulm, Sekretariat Prof. Kreienberg, Pritwitzstrasse 43, 89075 Ulm, Germany. FAX: 49 731 500 27602; christine-wulff{at}onlinehome.de

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