Elevated levels of Matrix Metalloproteinases tied to genesis of severe Preeclampsia: Study
Preeclampsia (PE) is a life-threatening condition for the mother, fetus, and newborn. PE induces multiple-organ damage to a woman's organs and systems in the second half of pregnancy (after 20 weeks) due to systemic endothelial dysfunction. The primary element in the development of PE is a disorder of placental formation, a process that occurs in the first 13 weeks of pregnancy, i.e., long before the first clinical manifestations of the symptoms. The leading cause of PE is incomplete trophoblast invasion and remodeling of the spiral arteries, which lead to unstable perfusion of the intervillous space, ischemic and reperfusion damage of the placental tissue, and systemic oxidative stress. This complex process is carried out due to the migration of extravillous trophoblast deep into the endometrium—termed cytotrophoblastic invasion. The reason for the incomplete reconstruction of the spiral arteries leading to PE is the insufficient activity of the lysing enzymes known as matrix metalloproteinases (MMPs).
MMPs are extracellular proteinases that play an important role in physiologic and pathologic processes: embryogenesis, implantation, placental formation, neoangiogenesis, and tumor transformation. With ongoing development during pregnancy, MMPs take part in the processes of blastocyst implantation, gestational transformation of the spiral arteries, and the formation of the placenta. Successful implantation occurs due to the ability of trophoblast cells to cleave the extracellular matrix components, in which MMPs are directly involved.
The second stage of PE is endothelial damage with the development of arterial hypertension (AH) and multiorgan damage due to the initiation of oxidative stress within the placenta, releasing pro- and antiangiogenic factors, with MMPs also referred to as antiangiogenic factors. MMPs damage the endothelium, cause systemic endothelial dysfunction, lead to AH, and can result in multiple-organ failure. The participation of MMPs in the development of hypertension is due to their influence on the vasoactive properties and architectonics of the vessel walls, as MMPs take part in the synthesis of the vasoconstrictor endothelin.
The current classification scheme differentiates PE into two variants. Early-onset PE (EO-PE) develops to and requires delivery at 34 weeks of gestation. The cause of EOPE is a placental factor that induces insufficient reconstruction of the spiral arteries during the second wave of trophoblast invasion, decreased perfusion of the intervillous space, and placental ischemia with the development of oxidative stress. Late-onset PE (LO-PE) appears after 34 weeks of pregnancy as a metabolic syndrome and is not associated with the formation and functioning of the placenta in the second half of pregnancy. Rather, it is manifested by increased blood pressure, proteinuria, and edema. Studies on the role of MMPs in PE are few and ambiguous, and therefore, in the present study, Elena Timokhina aimed to study the role of MMP types 2 and 9 in the development of severe PE with an early vs. late onset.
Authors conducted a retrospective study that included 92 pregnant women at a gestational age of 26-38 weeks, of which the principal group consisted of 61 patients with severe PE. They divided the principal group into two subgroups: the first subgroup was designated the severe early-onset preeclampsia (EO-PE) group and consisted of 30 pregnant women. The second group was designated the severe late-onset preeclampsia (LO-PE) group, comprising 31 patients. Authors determined the plasma concentrations of MMPs 2 and 9 in the groups with an ELISA.
In the group of PE patients with both EO-PE and LOPE, the level of MMP-2 was significantly higher compared to the women undergoing normal pregnancy; and no significant differences were observed when compared the levels of MMP-2 in the subgroups with EO-PE and LO-PE. Analysis of the concentrations of MMP-9 in EO-PE and LO-PE subgroups revealed attenuated levels of MMP-9 in both groups relative to the control group. A diminished level of MMP-9 was also noted in the EO-PE group compared to the LO-PE group.
In the current study, authors attempted to elucidate a potential role for MMPs in the genesis of severe PE and found that in the group of patients with both EO-PE and LO-PE, the levels of MMP-2 were significantly higher compared to the controls.
In this study, it was conversely found a decrement in the level of MMP-9 in pregnant women with PE, which is a metalloproteinase that is actively involved in remodeling of the spiral arteries at the first stage of PE development. The reduced levels of this enzyme in the plasma of pregnant women with PE thus reflect defective remodeling of the spiral arteries already at the first stage.
The identification of a significantly elevated level of MMP-2 during pregnancy complicated by PE is potentially important, as it enables targeted therapy in PE by using tissue inhibitors of MMP (TIMP-2). This inhibitor binds MMPs in plasma and thereby circumvents damage to the endothelium and averts the clinical manifestations of PE.
The findings of the study confirmed the role of MMP-2 and MMP-9 in the genesis of severe PE. EO-PE and LO severe PE were associated with an augmented concentration of MMP-2 and a commensurately attenuated level of MMP-9. The low levels of MMP-9 reflect inadequate angiogenesis in the formation of the placenta, which in turn leads to placental ischemia and oxidative stress—reflecting the first stage of the development of PE.
Authors found a significantly higher concentration of MMP-2 in patients with clinical features of severe PE, confirming the participation of MMP-2 in the second stage of PE implementation, i.e., endothelial damage, development of arterial hypertension, and multiple-organ damage. The significantly elevated level of MMP-2 obtained in pregnant women, both with EO-PE and LO severe PE, confirmed the development of endothelial dysfunction as an important element in the pathogenesis of polyorganic damage in PE. The future direction of this research entails an assessment of the progression of MMP levels in preeclamptic patients and the calculation of cut-off levels of MMPs for predicting complications of PE and the prognosis of adverse maternal outcomes.
Source: Elena Timokhina, Alexander Strizhakov, Sapiyat Ibragimova et al; Hindawi Journal of Pregnancy Volume 2020