Cellular and molecular regulation of spiral artery remodelling: lessons from the cardiovascular field

Abstract

A number of important changes take place in the maternal uterine vasculature during the first few weeks of pregnancy resulting in increased blood flow to the intervillous space. Vascular endothelial and smooth muscle cells are lost from the spiral arteries and are replaced by fetal trophoblast cells. Failure of the vessels to remodel sufficiently is a common feature of pregnancy pathologies such as early pregnancy loss, intrauterine growth restriction and pre-eclampsia. There is evidence to suggest that some vascular changes occur prior to trophoblast invasion, however, in the absence of trophoblasts remodelling of the spiral arteries is reduced. Until recently our knowledge of these events has been obtained from immunohistochemical studies which, although extremely useful, can give little insight into the mechanisms involved. With the development of more complex in vitro models a picture of events at a cellular and molecular level is beginning to emerge, although some caution is required in extrapolating to the in vivo situation. Trophoblasts synthesise and release a plethora of cytokines and growth factors including members of the tumour necrosis factor family. Studies suggest that these factors may be important in regulating the remodelling process by inducing both endothelial and vascular smooth muscle cell apoptosis. In addition, it is evident from studies in other vascular beds that the structure of the vessel is influenced by factors such as flow, changes in the composition of the extracellular matrix, the phenotype of the vascular cells and the local immune cell environment. It is the aim of this review to present our current knowledge of the mechanisms involved in spiral artery remodelling and explore other possible pathways and cellular interactions that may be involved, informed by studies in the cardiovascular field.

Fig. 1

Diagram of possible mechanisms involved in trophoblast-dependent spiral artery remodelling. Prior to remodelling low-flow, high-resistance spiral arteries are maintained in a stable state by interactions and signalling between endothelial cells (EC), the extracellular matrix (ECM) and vascular smooth muscle cells (VSMC). The decidualisation process causes EC vacuolation and VSMC swelling (not shown); however, the major changes to vessel structure occur after extravillous trophoblast reach the vessel. Trophoblasts invading interstitially would interact with VSMC first while endovascular trophoblasts would initially encounter EC in the vessel lumen. Trophoblasts can produce pro-apoptotic factors which can induce vascular cell apoptosis. Apoptotic cells may then be rapidly removed by professional phagocytes such as macrophages or other cells, such as trophoblasts, which also possess phagocytic activity. Proteolytic enzymes produced by trophoblasts and vascular cells can influence the composition of the ECM proteins important in maintaining vessel integrity. In particular matrix metalloproteinases (MMP) can be produced by trophoblasts and their production by VSMC can be regulated by trophoblasts. Loss of adhesive interactions between vascular cells and the remodelled ECM could then lead to vascular cell apoptosis. Changes in the ECM or signals from trophoblasts may influence the state of differentiation of VSMC by promoting a switch from a contractile to a more synthetic, proliferative phenotype, which may also be accompanied by increased migratory activity and sensitivity to pro-apoptotic factors. Haemodynamic factors and the presence of decidual natural killer cells will also play a role in the regulation of remodelling (not shown). The high-flow, low-resistance remodelled vessel will consist of trophoblasts embedded in a fibrinoid material as a replacement for the VSMC. The endothelium is temporarily replaced with a trophoblast layer, although it is restored later in pregnancy.