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.

Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis

“…Although Zhang et al (2013) suggest that a single mechanism regulates angiogenic functions of uNK cells, more research is needed to address this question. Kim et al (2013) conclude from studies using a VEGF-trap approach that hypoxia is not a regulator of angiogenesis in early mouse decidua.…”

“…It encodes seven distinct proteins (VEGFA, B, C, D, E, F, and PGF) with VEGFA as the main regulator of angiogenesis in numerous tissues. VEGFA is highly expressed in the uteroplacental unit, particularly during early pregnancy, and is an essential mediator of decidual angiogenesis (Kim et al 2013). Indeed, VEGFA is the only family member characterized as embryonic lethal when genetically ablated in mice (Bellomo et al 2000, Carmeliet et al 2001, Karkkainen et al 2004, Haiko et al 2008.…”

“…NKG2D is an NK cell activation receptor that recognizes MHC class I-related molecules but not MHC itself (Raulet et al 2013). Although flow cytometric studies report that NKG2D is more weakly expressed by angiogenic DBA C than by DBA K uNK cells (Yadi et al 2008), anti-NKG2D antibody treatment depleted DBA C uNK cells, decreased vessel density, and prevented vascular sinus formation in the central mesometrial decidua (Kim et al 2013). …”

Association of angiogenic cytokines (VEGF-A and VEGF-C) and clinical characteristic in women with unexplained recurrent miscarriage

“…VEGF regulates proliferation, differentiation, and survival of endothelial cells and enhances vascular permeability (11). VEGF-A consists of at least six isoforms through alternative splicing in humans (121, 145,165, 183, 189, and 206 amino acids), which have different biological properties and bioavailability (12).…”

Maternal obesity drives functional alterations in uterine NK cells

“…of uNK cells in pregnancy, where genetic ablation (19,20) or functional inactivation (21) of uNK cell subsets results in profound defects in decidual bed arterial remodeling and impaired angiogenesis. In particular, uNK cell interactions with fetal-derived trophoblasts are important for appropriate uNK cell activation (22,23), resulting in the subsequent secretion of proinflammatory cytokines (IFN-γ, TNF-α, and angiokines [placental growth factor and VEGF-A and -C]) (21,24).…”