Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm?

Abstract

Pre-eclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause pre-eclampsia. This review provides an alternative to the 'two-stage model' of pre-eclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (sFlt-1 also known as sVEGFR) and very low placenta growth factor (PlGF) are unique to pre-eclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking, pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the 'accelerator'. The 'braking system' includes the protective pathways of haem oxygenase 1 (also referred as Hmox1 or HO-1) and cystathionine-γ-lyase (also known as CSE or Cth), which generate carbon monoxide (CO) and hydrogen sulphide (H2S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, pre-eclampsia is an accelerator-brake defect disorder. CO and H2S hold great promise because of their unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble endoglin as well as to promote PlGF and endothelial NOS activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line.

Figure 1

Effect of defective protective pathways in pre-eclampsia. This diagram illustrates that the defect in HO-1 (also referred to as Hmox) and CSE (also known as Cth), which generates signalling molecules, CO and H₂S, and which results in an increase in sVEGFR-1 and sEng as well as a decrease in PlGF production. These are key factors responsible for vascular dysfunction in pre-eclampsia.

Figure 2

The accelerator and brake theory of pre-eclampsia. Schematic diagram to illustrate the sequence of events involved in the pathogenesis of pre-eclampsia. The upstream events consist of dysregulation of endogenous protective pathways – ‘the brakes’ – [CSE which generates H₂S and HO-1 that produces CO] leading to maternal endothelial activation. As a consequence, there is an increase in anti-angiogenic factors – ‘the accelerator’ – (sVEGFR-1, sEng and soluble E-slectin and a decrease in angiogenic factors PlGF and eNOS, which generates NO). These biochemical changes lead to a generalized endothelial dysfunction, renal injury and generation of reactive oxygen species, which precedes the clinical onset of pre-eclampsia. After 20 weeks of gestation, the clinical symptoms manifest themselves as high BP and proteinurea, which are concurrent with excessive inflammation as indicated by increase in pro-inflammatory cytokines (Th1 cytokine production) and ET-1 release.