Pre-Eclampsia: Clinical Manifestations and Molecular Mechanisms

Abstract

Preeclampsia affects 3–5% of pregnancies and can have a significant impact on health for both mother and fetus. Risk factors include maternal co-morbidities such as obesity and chronic hypertension, paternal factors, and genetic factors. New hypertension and proteinuria during the second half of pregnancy are key diagnostic criteria, but the clinical features and associated prognostic implications are somewhat heterogeneous and may reflect different mechanisms of disease. Renal dysfunction and proteinuria correspond to the pathologic finding of glomerular endotheliosis, and generally resolve after cure of preeclampsia through fetal and placenta delivery. The molecular mechanisms behind this disease are being discovered and refined. The initial etiologic agents are currently unknown. Pathologic studies show abnormal development of an ischemic placenta with a high-resistance vasculature, which cannot deliver an adequate blood supply to the fetoplacental unit. Endothelial dysfunction plays a central role in the pathogenesis of the maternal syndrome. Dysfunctional endothelial cells produce altered quantities of vasoactive mediators, which lead to a tip in the balance towards vasoconstriction. An imbalance in circulating angiogenic factors is emerging as a prominent mechanism that mediates the endothelial dysfunction and the clinical signs and symptoms of preeclampsia. Soluble fms-like tyrosine kinase 1 (sFlt1), an endogenous anti-angiogenic factor that is a potent vascular endothelial growth factor (VEGF) antagonist, is highly elevated in preeclampsia. VEGF is not only important in angiogenesis, but also in maintaining endothelial health including the formation of endothelial fenestrae (a hallmark of the glomerular vascular endothelium). sFlt1 overexpression in animals induces glomerular endotheliosis with the loss of endothelial fenestrae that resembles the renal histological lesions of preeclampsia. More severe forms of preeclampsia, including the HELLP syndrome, may be explained by a concomitant elevation in both sFlt1 and soluble endoglin, another anti-angiogenic factor. Unraveling of the molecular mechanisms behind preeclampsia may help to expand our armamentarium to treat patients in a more directed fashion, as current management consists of supportive care and expedited delivery. Finally, long-term outcomes of women with preeclampsia include a significantly increased risk for hypertension and cardiovascular disease, including mortality, which may warrant more aggressive screening and treatment in this population.

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

“…Consequently, we propose the hypothesis that leakage of fluids and proteins could result in edema and proteinuria, conditions observed in women with preeclampsia. 41,42 The maternal vascular system undergoes an inflammatory process during preeclampsia, as evidenced by increased neutrophil activation [43][44][45][46] and vascular neutrophil infiltration. 6 -8 In the early phase of this study, we hypothesized that infiltrating neutrophils could affect expression of genes related to the extracellular matrix.…”

Pregnancy after Kidney Transplantation

“…Preeclampsia causes severe maternal and fetal complications, such as renal failure, HELLP syndrome (hemolysis, elevated liver enzymes, and thrombocytopenia), seizures, liver failure, stroke, or death for the mother. For the fetus, preeclampsia can result in being small for gestational age, preterm delivery, hypoxic neurologic injury, or death (60). Diagnosis of preeclampsia is difficult in the gravid renal transplant recipient because BP commonly rises late in pregnancy and many patients have preexisting proteinuria (61).…”

“…In addition, associated features of hyperuricemia and edema are often coexistent in renal transplant patients (62). It is interesting that histologic and molecular information show that preeclampsia is a disorder of placental hypoxia and endothelial dysfunction, although many mechanisms are yet unknown (60,63). Whether markers of preeclampsia such as angiogenic or antiangiogenc proteins will provide specific markers for preeclampsia is unknown but could provide a very important area for future study.…”

Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

“…20 -22 Two important antiangiogenic factors produced in the placenta gain access to the maternal circulation and are involved in the pathogenesis of preeclampsia. [23][24][25] First, soluble fms-like tyrosine kinase-1 (sFLT-1) is a splice variant of the vascular endothelial growth factor receptor that captures vascular …”

“…20 -22 Two important antiangiogenic factors produced in the placenta gain access to the maternal circulation and are involved in the pathogenesis of preeclampsia. [23][24][25] First, soluble fms-like tyrosine kinase-1 (sFLT-1) is a splice variant of the vascular endothelial growth factor receptor that captures vascular endothelial growth factor, 26,27 thus preventing its interaction with ligands and downregulating the biological effects of vascular endothelial growth factor, such as angiogenesis 28 and stimulation of NO synthesis by endothelial cells. 29 -31 Second, although soluble endogline (sEng) is found in healthy pregnancies, its concentrations increase in preeclampsia.…”