Abstract
IntroductionPlacental protein 13 (PP13), a placenta specific protein, is reduced in the first trimester of pregnancy in women who subsequently develop preeclampsia. A naturally occurring PP13 deletion of thymidine at position 221 (DelT221 or truncated variant) is associated with increased frequency of severe preeclampsia. In this study we compared the full length (wildtype) PP13 and the truncated variant.MethodsFull length PP13 or its DelT221 variant were cloned, expressed and purified from E-Coli. Both variants were administrated into pregnant rats at day 8 of pregnancy for slow release (>5 days) through osmotic pumps and rat blood pressure was measured. Animals were sacrificed at day 15 or day 21 and their utero-placental vasculature was examined.ResultsThe DelT221 variant (11 kDA) lacked exon 4 and a part of exon 3, and is short of 2 amino acids involved in the carbohydrate (CRD) binding of the wildtype (18 kDA). Unlike the wildtype PP13, purification of DelT221 variant required special refolding. PP13 specific poly- clonal antibodies recognized both PP13 and DelT221 but PP13 specific monoclonal antibodies recognized only the wildtype, indicating the loss of major epitopes. Wildtype PP13 mRNA and its respective proteins were both lower in PE patients compared to normal pregnancies. The DelT221 mutant was not found in a large Caucasian cohort. Pregnant rats exposed to wildtype or DelT221 PP13 variants had significantly lower blood pressure compared to control. The wildtype but not the DelT221 mutant caused extensive vein expansion.ConclusionThis study revealed the importance of PP13 in regulating blood pressure and expanding the utero-placental vasculature in pregnant rats. PP13 mutant lacking amino acids of the PP13 CRD domain fails to cause vein expansion but did reduce blood pressure. The study provides a basis for replenishing patients at risk for preeclampsia by the full length but not the truncated PP13.
Highlights
Placental protein 13 (PP13), a placenta specific protein, is reduced in the first trimester of pregnancy in women who subsequently develop preeclampsia
According to the WHO preeclampsia remains a major reason for mortality and morbidity of mothers, fetuses and neonates [1]
Recent studies have indicated that one of the major causes of placental pathology underlying preeclampsia is the non-homogeneous expansion of the utero-placental vasculature, causing irregular and pulsating blood supply to the placenta, associated with villous disruption and damage [6] that is further exacerbated by the increased impedance of blood flow and the impact of various maternal and placental derived polypeptides and small molecules [4,5]
Summary
Placental protein 13 (PP13), a placenta specific protein, is reduced in the first trimester of pregnancy in women who subsequently develop preeclampsia. Recent studies have indicated that one of the major causes of placental pathology underlying preeclampsia is the non-homogeneous expansion of the utero-placental vasculature, causing irregular and pulsating blood supply to the placenta, associated with villous disruption and damage [6] that is further exacerbated by the increased impedance of blood flow and the impact of various maternal and placental derived polypeptides and small molecules [4,5]. Among these factors is Placental Protein 13 (PP13). A meta-analysis by Huppertz et al 2013 [7] that was based on 18 studies revealed that low levels of this protein are associated with an increased risk to develop preeclampsia
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