Angiogenic factors and preeclampsia

Abstract

Preeclampsia, a hypertensive disorder peculiar to pregnancy, is a systemic syndrome that appears to originate in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of phenotypic preeclampsia was largely unknown, but recent observations support the hypothesis that altered expression of placental anti-angiogenic factors are responsible for the clinical manifestations of the disease. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These anti-angiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and as of 2011 the role of angiogenic proteins in early placental vascular development was starting to be explored. The data linking angiogenic factors to preeclampsia have exciting clinical implications, and likely will transform the detection and treatment of preeclampsia.

Figure 1

Glomerular changes in preeclampsia. Comparison between a rat model induced with anti-angiogenic proteins and the human disease. (A) Normal human glomerulus (hematoxylin-eosin). (B) Glomerular changes in preeclampsia (hematoxylin-eosin). A 33-year-old woman with twin gestation and severe preeclampsia at 26 weeks' gestation with a urine protein/creatinine ratio of 26 at the time of biopsy. (C) Glomerular changes in preeclampsia (electron microscopy). Note occlusion of capillary lumen cytoplasm and expansion of the subendothelial space with electron dense material. Podocytes show protein resorption droplets and relatively intact foot processes. Original magnification, 1,500×. (D) Animal model of preeclampsia: control rat glomerulus (hematoxylin-eosin). Note normal cellularity and open capillary loops. (E) Animal model of preeclampsia: sFlt1-treated rat glomerulus (hematoxylin-eosin). Note occlusion of capillary loops by swollen cytoplasm with minimal increase in cellularity. (F) Animal model of preeclampsia: sFlt1-treated rat glomerulus (electron microscopy). Note occlusion of capillary loops by swollen cytoplasm with relative preservation of podocyte foot processes. Original magnification, 2,500×. All light micrographs were taken at an identical original magnification of 40×. Reproduced with permission from Karumanchi et al.[dvc13]

Figure 2

sFlt1 and sEng cause endothelial dysfunction by antagonizing VEGF and TGF-β1 signaling. Under physiologic conditions, and during normal pregnancy, VEGF and TGF-β1 maintain endothelial health by interacting with their endogenous endothelial receptors. In preeclampsia, excess placental secretion of sFlt1 and sEng inhibit VEGF and TGF-β1 signaling, respectively, in the vasculature. This results in endothelial cell dysfunction, including decreased prostacyclin, nitric oxide production, and release of procoagulant proteins. Reproduced with permission from Karumanchi and Epstein.

Figure 3

Hypothetical framework for the pathogenesis of preeclampsia. Placental dysfunction, triggered by poorly understood mechanisms—including genetic, immunologic, and environmental—plays an early and primary role in the development of preeclampsia. Alterations in regulatory factors including HO, catechol-o-methyltransferase(COMT)/2-methoxyestradiol (2ME), and angiotensin type 1 agonistic autoantibodies (AT1AA) lead to excess placental secretion of angiogenic factors into the maternal circulation. These factors lead to impaired VEGF/PlGF and TGF-β signaling, resulting in systemic endothelial cell dysfunction mediated by a variety of factors, as shown. Endothelial dysfunction, in turn, results in the systemic manifestations of preeclampsia. Reproduced with permission from Maynard and Thadhani.[dvc14]