Vessel Re-modelling

Vascular remodelling of resistance arteries typically involves medial thickening through hyperplasia of smooth muscle cells (SMC) and deposition of extra-cellular matrix. The result is a reduction in lumen diameter and increased resistance. In human pregnancy the opposite occurs when the uterine spiral arteries are remodelled. There is loss of both endothelium and SMC resulting in medial ablation, luminal expansion and a decrease in resistance. The factors that influence vessel remodelling can be classified as cellular, micro-environmental or genetic. In pregnancy, the cellular effect, namely the presence of the trophoblast, is the most important factor that determines the outcome of remodelling. Due to the scarcity of appropriate tissue and models, little work has been done to understand the basics of spiral artery remodelling in human pregnancy. Recent work on pregnant rats has identified features that suggest they could be a useful model for future investigations into the fundamental mechanisms of remodelling in human pregnancy.

Shallow or incomplete trophoblast invasion with limited vessel remodelling have been associated with complications of human pregnancy such as pre-eclampsia. Work on spiral artery remodelling has focussed on defects that may lead to this outcome however little is known about the basis of remodelling in normal pregnancy. Our laboratory has been able to demonstrate that primary cytotrophoblast can initiate SMC apoptosis in spiral arteries via the Fas/Fas ligand pathway. A trophoblast-dependent apoptotic mechanism could thus contribute to SMC loss during remodelling. Apoptosis is a slow and gradual event, typically involving single cells which can take upwards of 24 hours to die following an initial apoptotic signal. Apoptosis thus proceeds in an asynchronous manner leading to a cumulative effect. This is in keeping with the time course of spiral artery remodelling in vivo which is a gradual process occurring over a period of weeks.

Many factors will affect the interactions between trophoblast and SMC. Secreted chemokines may attract trophoblast to SMC and recent work has identified a role for the eph/ephrin family in stimulating trophoblast invasion. Placental hormones such as human placental lactogen and human chorionic gonadotropin (hCG) may act to positively or negatively regulate SMC apoptosis. hCG has been reported to both protect cells from apoptosis and to increase apoptosis. Cytokines found in the maternal-fetal environment can alter expression of apoptotic ligands such as TNF-related apoptosis-inducing ligand (TRAIL) which is produced by trophoblast and is up-regulated by TNF-alpha and IFN-gamma stimulation.

Spiral artery remodelling in pregnancy thus relies on a complex co-ordination of micro-environmental factors, cell-cell interactions and apoptotic events over an extended time frame that maintains vessel integrity. The end result is a unique transformation of maternal vessels which is essential for the maintenance of a successful pregnancy.

 

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