A longitudinal study of circulating angiogenic and antiangiogenic factors and AT1-AA levels in preeclampsia

Abstract

Our earlier studies of preeclampsia (PE) at delivery have demonstrated the alteration of one carbon cycle, reduced placental omega 3 fatty acids, altered circulating levels of angiogenic factors and differential placental gene-specific methylation patterns of angiogenic factors. This study was undertaken to examine changes in the levels of angiogenic factors and angiotensin II type 1 receptor autoantibodies (AT1-AAs) throughout gestation, from early pregnancy until delivery, in women with PE and to examine their association with cord angiogenic factors, blood pressure and infant weight. A total of 81 pregnant women (46 normotensive and 35 with PE) were followed at three different time points during pregnancy: 16-20 weeks (T1), 26-30 weeks (T2) and at the time of delivery (T3). The plasma levels of angiogenic factors and AT1-AAs were determined in the maternal and cord plasma by commercial enzyme-linked immunosorbent assay kits. Maternal plasma levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were lower (P<0.05 for both), whereas soluble fms-like tyrosine kinase-1 (sFlt-1; P<0.05) and the sFlt-1/PlGF ratio (P<0.01) were higher in early pregnancy in the PE group. Maternal plasma AT1-AA levels were higher (P<0.05) at T2 in women with PE. Cord plasma VEGF and soluble kinase insert domain receptor (sKDR) levels were lower (P<0.01 and P<0.05, respectively), whereas AT1-AA levels were higher (P<0.05) in the PE group. Maternal plasma VEGF levels in early pregnancy were positively associated with systolic blood pressure, whereas the sFlt-1/PlGF ratio at T2 was negatively associated with infant weight in the PE group. Low levels of proangiogenic factors (VEGF and PlGF) and high levels of AT1-AAs and antiangiogenic factors (sFlt-1 and sFlt-1/PlGF ratio) are present in the maternal circulation during early gestation in women with PE.

Increased neuronal seizure activity correlates with excessive systemic inflammation in a rat model of severe preeclampsia

“…Several key events have been shown to be involved in the early development of PE, including insufficient spiral artery remodeling and higher plasma levels of soluble fms-like tyrosine kinase-1. Higher plasma levels of soluble fms-like tyrosine kinase-1 has been shown to antagonize vascular endothelial growth factor, which causes abnormal spiral artery remodeling [31][32][33] ; therefore, vascular endothelial growth factor inhibitors have been used as a model of PE. 34,35 In addition, based on two predominant theories of PE (the locally chronic uterine placenta ischemia and hypoxia theory and the excessive activation of the maternal immune system theory), additional animal models of PE have been developed.…”

Decreased circulating anandamide levels in preeclampsia

“…Increasing evidence suggests that an exaggerated maternal systemic inflammatory response to pregnancy with an increase in the ratios of peripheral blood Th1/Th2 and Th17/ regulatory T cells, a systemic oxidative stress, as well as an imbalance between circulating angiogenic and anti-angiogenic factors plays a crucial role in the pathogenesis of the disease. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Endocannabinoids are endogenous ligands that bind to the similar receptor as delta-9-tetrahydrocannabinol (Δ 9 -THC), the most potent psychotropic constituent of marijuana. The most studied endocannabinoid is N-arachidonoylethanolamine (also known as anandamide), which is reported to have a central role in female reproduction, particularly in decidualization, 17 oviductal transport, 18 preimplantation embryo development, 19 timely embryo implantation and ensuring receptive uterine environment.…”

Preeclampsia and Vascular Function: A Window to Future Cardiovascular Disease Risk

“…Women with or who go on to develop preeclampsia exhibit low serum concentrations of free PlGF and VEGF and high concentrations of sFlt-1. 23,26 Additional research has also shown that the ratio of sFlt-1 to PlGF is a better marker of preeclampsia than either measure alone, with a higher ratio indicating increased risk. 29,30 A recent study did not find that the assessment of changes in angiogenic markers between first and second trimesters alone improved the prediction of preeclampsia.…”

“…22 Preeclampsia is also characterized by an imbalance or deficit in growth factors promoting angiogenesis. 23,24 Growing evidence suggests that inadequate trophoblast invasion of the uterine spiral arteries leads to placental ischemia, 25 which, in turn, initiates the release of the antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1 binds and inhibits angiogenic factors, such as vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF).…”