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Possible Angiogenic Roles of Insulin-Like Growth Factor II and Its Receptors in Uterine Vascular Adaptation to Pregnancy

Department of Obstetrics and Gynecology (F.H., O.D.L., J.H., U.L., M.Z.), Justus-Liebig-University of Giessen, D-35385 Giessen, Germany; Department of Biochemistry (O.D.L., K.T.P.), Medical Faculty, Justus-Liebig-University of Giessen, D-35385 Giessen, Germany; and Medical Research Council Group in Fetal and Neonatal Health and Development (V.K.M.H.), Child Health Research Institute, University of Western Ontario, London N6A 4V2, Canada

Address all correspondence and requests for reprints to: Marek Zygmunt, M.D., Ph.D., Department of Obstetrics and Gynecology, University of Giessen, Klinikstr. 32, D-35385 Giessen, Germany. E-mail: marek.t.zygmunt{at}gyn.med.uni-giessen.de.

Adaptation of the maternal uterine vasculature is essential for normal fetal and placental development in which angiogenesis is considered one of the most critical adaptive changes during pregnancy. Highly expressed in cytotrophoblasts and maternal endothelial cells during pregnancy, IGF-II promotes cell migration and regulates fetal and placental growth. We hypothesized that IGF-II regulates uterine angiogenesis during pregnancy. Both uterine vasculature and isolated uterine microvascular endothelial cells expressed high levels of IGF-II and IGF-II/mannose-6 phosphate receptor mRNA as shown by in situ hybridization. Physiological concentrations of IGF-II significantly increased vessel formation, as shown by a three-dimensional angiogenesis assay in vitro or a chicken chorionallantoic membrane assay in vivo. The angiogenic response of IGF-II could be reversed by the addition of ß-galactosidase or rabbit-antihuman IGF-II/M6P receptor antiserum, whereas blocking antibodies against IGF-I receptor or insulin receptor influenced IGF-II-induced sprout formation. IGF-II promoted migration of endothelial cells (10–250 ng/ml) tested in a modified Boyden chamber, but no stimulating effect on proliferation was observed. The application of several intracellular signal transduction molecules and their inhibitors indicated that protein kinase C and G_i protein might play a role in the IGF-II-induced angiogenesis. Our results suggest an important angiogenic role of IGF-II in the vascular adaptation to pregnancy.

This work was supported by grants from the German Research Council (DFG) (to M.Z. and K.T.P.), the Wilhelm-Sander-Foundation (to K.T.P.), and the Medical Research Council (to V.K.M.H.).

Abbreviations: bFGF, Bovine fibroblast growth factor; CAM, chicken chorioallantoic membrane; FCS, fetal calf serum; hCG, human chorionic gonadotropin; IGFBP, IGF-binding protein; IGF-IR, IGF-I receptor; IR, insulin receptor; mAb, monoclonal antibody; MC, microcarrier; M6PR, mannose-6 phosphate receptor; PDBu, phorbol,12,13-dibutyrate; PKA, protein kinase A; PKAI, PKA inhibitory peptide; PKC, protein kinase C; PKCI, PKC inhibitory peptide; UMVEC, uterine microvascular endothelial cell; VEGF, vascular endothelial growth factor; VI, vascularity index.

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