MMP-12-mediated vascular elastolysis - a potential target for therapeutic intervention in complicated pregnancies

Normally, blood flow is controlled by stretchy, elastic fibres in the walls of blood vessels that allow them to become wider or narrower, as required. In pregnancy, the developing baby needs a constant supply of blood, so elastic fibres in the blood vessels of the womb are broken down and the vessels are permanently widened. If this process does not happen, it can cause the baby to be born too small or too early and can make the mother seriously ill. We have identified one of the proteins that controls breakdown of elastic fibres in the womb and we will study different ways to increase its activity. This will lead to development of a treatment to make blood vessels in the womb wider, if the process does not happen naturally.

During pregnancy, the uterine spiral arteries are remodelled to ensure a constant supply of blood is delivered to the developing placenta at an optimal rate of flow. Breakdown of elastic fibres in the arterial wall is crucial to facilitate a permanent increase in vessel diameter and to abolish maternal vasomotor control. Impaired vascular remodelling is associated with second trimester miscarriage, pre-eclampsia, preterm labour and fetal growth restriction. We have evidence to suggest that elastin breakdown is mediated by trophoblast- and vascular smooth muscle cell-derived matrix metalloproteinase-12 (MMP-12). In this proposal we will: [i] analyse MMP-12 expression and activity in the placentas and spiral arteries obtained from normal and complicated pregnancies, [ii] investigate the regulation of MMP-12 expression and activity by elastin-derived peptides, and [iii] manipulate MMP-12 activity in ex vivo tissue models to promote spiral artery remodelling.