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Uterine spiral artery muscle dedifferentiation
A Robson1,2, G E Lash1,3, B A Innes1
1Reproductive and Vascular Biology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Human Reproduction (Oxford, England)
|July 27, 2019
Summary
Vascular smooth muscle cell (VSMC) dedifferentiation is a key feature of uterine spiral artery (SpA) remodelling in early human pregnancy. Uterine natural killer (uNK) cells and extravillous trophoblast cells (EVTs) drive this process through the secretion of Ang-1 and Ang-2.
Area of Science:
- Reproductive biology and immunology
- Vascular remodeling in pregnancy
- Cellular differentiation and plasticity
Background:
- Uterine spiral arteries (SpAs) undergo significant morphological changes during early human pregnancy.
- The precise role of vascular smooth muscle cells (VSMCs) in SpA remodeling remains unclear.
- Existing evidence suggests uterine natural killer (uNK) cells are involved in SpA remodeling.
Purpose of the Study:
- To investigate whether VSMC dedifferentiation is a characteristic of human SpA remodeling in early pregnancy.
- To explore the potential role of uNK cells and extravillous trophoblast cells (EVTs) in initiating VSMC dedifferentiation.
- To examine the involvement of angiogenic growth factors (AGFs) in this process.
Main Methods:
- Immunohistochemical analysis of placental bed biopsies to assess VSMC differentiation markers and AGF receptors in SpAs.
- Development of an in vitro model using chorionic plate arteries (CPAs) to study VSMC differentiation.
- Exposure of CPAs to conditioned media from uNK cells, EVTs, co-cultures, and specific AGFs (Ang-1, Ang-2, VEGF).
Main Results:
- SpA VSMCs in partially remodeled arteries showed increased expression of Tie-2, VEGF-R2, and osteopontin, with decreased expression of contractile markers (α-SMA, H-Cal, MyHC, smoothelin).
- In vitro, uNK cell and EVT conditioned media, particularly from later gestational ages (12-14 weeks), induced VSMC dedifferentiation (reduced contractile markers, increased osteopontin).
- Ang-1 and Ang-2 directly reduced VSMC contractile marker expression (H-Cal), and their inhibition in uNK cell supernatants blocked this effect.
Conclusions:
- VSMC dedifferentiation is a significant feature of early human SpA remodeling.
- uNK cells and EVTs play crucial roles in SpA remodeling by secreting Ang-1 and Ang-2, which induce VSMC dedifferentiation.
- This study provides novel insights into the direct involvement of Ang-1 and Ang-2 in VSMC biology during pregnancy.
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