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

Minah Kim,Gou Young Koh,Youngsok Choi,Hoon‐Ki Sung,Napoleone Ferrara,Kyu Rae Kim,Hyeung Ju Park,Kari Alitalo,John P Lydon,Francesco J Demayo,Jeon Yeob Jang,Masabumi Shibuya,Young‐Suk Cho,Andras Nagy,Jae Won Seol

doi:10.1002/emmm.201302618

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.

Highlights

The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined
Decidual angiogenesis is mainly regulated through vascular endothelial growth factor (VEGF)-A secreted from the progesterone receptor (PR)-expressing decidual stromal cells which are largely distributed in the anti-mesometrial region (AMR)
We found that the VEGF‐A/VEGFR2 system plays a critical role in decidual angiogenesis and vascular sinus folding’ (VSF) remodelling, and we tried to clarify how VEGF‐A expression is regulated in decidual stromal cells (DSCs)

Summary

Introduction

The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. 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. The roles of P4, E2 and their receptors in decidual angiogenesis have been studied, but they appear to vary depending on species, timing and experimental design (Das et al, 2009; Girling et al, 2007; Heryanto & Rogers, 2002; Walter et al, 2005), and have not yet been firmed established It is unknown how P4 and E2 affect the VEGF‐A‐VEGFR2 system in a spatiotemporal manner to promote decidual angiogenesis during early pregnancy. During the postpartum period, the uterus undergoes rapid shrinkage with strong contractile activity and endometrium normalization, but little is known about the exact characteristics and regulations of vascular remodelling and regression in the endometrium

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Results

Conclusion