VEGF‐A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy

• Published in: EMBO molecular medicine 2013-09, Vol.5 (9), p.1415-1430
• Main Authors: Kim, Minah, Park, Hyeung Ju, Seol, Jae Won, Jang, Jeon Yeob, Cho, Young‐Suk, Kim, Kyu Rae, Choi, Youngsok, Lydon, John P., DeMayo, Francesco J., Shibuya, Masabumi, Ferrara, Napoleone, Sung, Hoon‐Ki, Nagy, Andras, Alitalo, Kari, Koh, Gou Young
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Decidua; Decidua - drug effects; Decidua - physiology; decidual angiogenesis; Elongation; Embryos; Endometrium; Enlargement; Female; Growth factor receptors; Implantation; Intussusception; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Natural killer cells; Neovascularization, Physiologic; Postpartum; Postpartum period; Pregnancy; pregnant uterus; Progesterone; Progesterone - metabolism; Research Article; Stromal cells; Uterus; Variance analysis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular endothelial growth factor receptors; vascular regression; vascular sinus folding; VEGF‐A
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201302618

The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of ‘vascular sinus folding’ (VSF) and mural cell drop‐out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy — just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF‐A secreted from the progesterone receptor (PR)‐expressing decidual stromal cells which are largely distributed in the anti‐mesometrial region (AMR). In comparison, P 4 ‐PR‐regulated VEGF‐A‐VEGFR2 signalling, ligand‐independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand‐independent manner, with marked reduction of VEGF‐A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors — VEGFR2 and Tie2 — strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner. Graphical Abstract VEGFR2 and Tie2 differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri, questioning the use of treatments affecting these pathways during pregnancy and postpartum.