title: VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy.
abstract: 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, P4 -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.
authors.affiliation: Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Minah
authors.initials: M
authors.lastname: Kim
authors.forename: Hyeung Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Seol
authors.forename: Jeon Yeob
authors.initials: JY
authors.lastname: Jang
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Cho
authors.forename: Kyu Rae
authors.initials: KR
authors.lastname: Kim
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: Demayo
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Hoon-Ki
authors.initials: HK
authors.lastname: Sung
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D000818:Animals; D003656:Decidua / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D011374:Progesterone
keywords: VEGF-A; decidual angiogenesis; pregnant uterus; vascular regression; vascular sinus folding