Anti-angiogenic collagen fragment arresten is increased from 16 weeks' gestation in pre-eclamptic plasma
Introduction
Pre-eclampsia (PE) is a serious pregnancy complication with no known cause. PE is characterised by new onset hypertension and proteinuria after 20 weeks' gestation in a previously normotensive woman [1], [2]. PE affects between 2 and 8% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality worldwide [3]. The only cure for PE is the removal of the placenta [4]. Approximately 5% of women with PE also develop the haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, which can progress rapidly to become life-threatening [5], [6]. Another complication that may develop from PE is eclampsia, where the woman suffers from seizures that may lead to death [5]. Depending on the severity of the mother's condition, the fetus may need to be delivered prematurely. Over 40% of medically indicated preterm births are attributed to PE [7]. Preterm births are associated with adverse outcomes including increased risks of neonatal death, poor long term health and delayed mental development outcomes [8].
Our previous genetic linkage studies identified COL4A1 and COL4A2 as maternal PE susceptibility genes [9]. COL4A1 and COL4A2 code for type IV collagen α chain 1 and α chain 2 respectively. The mRNA expression levels of these genes are significantly increased in PE decidua and these increased levels correlate with an earlier onset of PE [10]. The α1 and α2 chains form a triple helix isoform [α1(IV)]2α2(IV), which is expressed in all basement membranes [11]. Type IV collagen forms the scaffolding of basement membranes in tissues, allowing other basement membrane proteins to be incorporated and for cell interaction to occur with the basement membrane [11]. Type IV collagen is detectable in maternal blood and is significantly increased in third trimester PE serum [12]. Serum collagen levels reflect the degradation of the basement membrane and damage to the endothelium [12].
Degradation of type IV collagen generates many protein fragments [13]. A study by Bieglmayer and Hofer [14] showed an increase of type IV collagen non-collagenous (NC1) domain fragments in third trimester PE serum. Circulating NC1 fragment levels are also increased in patients with autoimmune, metastatic tumour, liver and renal disease [15], [16]. These studies did not identify which of the six different α chains of type IV collagen was responsible for the observed increases. The six α chains of type IV collagen produce six distinct NC1 fragments, which are derived from the carboxyl terminus of the α chains [17]. NC1 fragments arresten (COL4A1), canstatin (COL4A2) and tumstatin (COL4A3) have anti-angiogenic effects that increase endothelial cell apoptosis and decrease endothelial cell proliferation, migration and tube formation [17], [18], [19]. Research on these fragments is currently focused on their potential as anti-cancer therapeutics by targeting tumour angiogenesis [20]. To date, the levels of each NC1 fragment of type IV collagen have not been investigated and their roles in pregnancy are unknown.
Our earlier findings showed increased decidual expression of COL4A1 and COL4A2 in PE, which correlated with an earlier onset of PE, a marker of clinical severity [10]. Having shown a link between PE and increased collagen expression, the study aims were to measure and compare the second and third trimesters levels of arresten and canstatin in the plasma of PE women compared with normotensive controls, to correlate these levels with clinical parameters relating to the severity of PE and to determine whether the maternal decidua was a source of these fragments.
Section snippets
Study criteria
PE was defined as pregnancy induced hypertension with a systolic pressure of ≥140 mmHg and/or a diastolic pressure of ≥90 mmHg, accompanied by proteinuria of ≥0.3 g in 24 h or a spot urine dipstick of ‘2+’ [21], [22]. Exclusion criteria were factors known to increase the risk of PE such as systemic lupus erythematosus and pre-existing hypertension. Blood pressures of normotensive patients were less than 140/90 mmHg. A non-treating obstetrician independently verified patient clinical records.
Patient characteristics
Analysis of the n = 30 normotensive and n = 14 PE patients in the second trimester cohort at delivery showed significant differences in gestational age after delivery and infant birth weight, but no significant difference in maternal age, gestational age at sampling, infant birth weight percentiles, gravidity, parity and infant sex (Table 1). Analysis for the n = 14 normotensive and n = 25 PE patients in the third trimester cohort after delivery showed significant differences in gestational age
Discussion
This is the first study to examine the levels of anti-angiogenic type IV collagen NC1 fragments arresten and canstatin in the plasma and decidua of normotensive and PE pregnant women. We demonstrated significant increases of the arresten fragment in plasma during the second trimester, several weeks before the onset of clinical disease and in the third trimester after the onset of clinical disease. The increase in arresten during the third trimester correlated with the requirement for magnesium
Acknowledgements
We thank all the patients and clinical research midwives who were involved with sample donation and collection. This study was supported by funding from The Royal Women's Hospital, Melbourne, Australia. H.E.J. Yong was supported by The University of Melbourne's Melbourne International Fee Remission Scholarship and the Felix Meyer Scholarship in Obstetrics and Gynaecology.
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Present Address: Department of Medicine, Monash University, Monash Medical Centre, Clayton 3168, Victoria, Australia.