Effects of Placental Protein 13 on the Cardiovascular System in Gravid and Non-Gravid Rodents

Gizurarson, Sveinbjörn; Huppertz, Berthold; Osol, George; Skarphedinsson, J. O.; Mandalà, Maurizio; Meiri, Hamutal

doi:10.1159/000345964

Cited by 31 publications

(42 citation statements)

References 31 publications

(76 reference statements)

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“…The pumps were implanted at gestational day 8 after loading with 127 ng rPP13 (n = 9), the DelT 221 variant (n = 6) or saline (n = 6). As described by Gizurarson et al 2013 [24] the pumps released approximately 0.625 ng PP13/h over 5–7 days (term = day 22).…”

Section: Methodsmentioning

confidence: 86%

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The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant

et al. 2014

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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.

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Section: Methodsmentioning

confidence: 86%

“…In a recent study, Gizurarson et al 2013 [24] have shown that pregnant rodents exposed to PP13 show a reduced blood pressure. In this paper we wanted to investigate whether beyond the immuno-tolerance impact, the CRD has an additional physiological and morphological impact during pregnancy that is associated with preeclampsia.…”

Section: Introductionmentioning

confidence: 95%

The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant

et al. 2014

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“…The current experiments were designed to extend the findings from a previous pilot study that showed that direct application of PP13 to isolated, pressurized rat uterine arteries elicited arterial vasodilation [30]. There, we also found some preliminary evidence to support a stimulatory effect on arterial remodeling secondary to a single in vivo injection in healthy nonpregnant rats starting late in pregnancy (day 13).…”

Section: Discussionsupporting

confidence: 60%

“…In our previous study [30], we have demonstrated arterial vasodilation and expansion. Here we focused on venous expansion.…”

Section: Discussionmentioning

confidence: 87%

“…Our previous study on the pharmacological effects of PP13 in gravid rats [30] showed that its administration leads to a reduction in arterial blood pressure, and may induce uterine artery vasodilatation, accompanied by changes or remodeling of the uterine vasculature; both effects would favor an augmentation of uteroplacental perfusion. This study raised the question whether PP13 may be used as a biopharmaceutical to prevent preeclampsia if it were administered to women having low levels of PP13 early in the first trimester of pregnancy.…”

Section: Introductionmentioning

confidence: 99%

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Placental Protein 13 Administration to Pregnant Rats Lowers Blood Pressure and Augments Fetal Growth and Venous Remodeling

Gizurarson

Sigurðardóttir

Meiri³

et al. 2015

Fetal Diagn Ther

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Reduced first-trimester concentrations of placental protein 13 (PP13) are associated with subsequent development of preeclampsia, a major pregnancy disorder. We previously showed that PP13 has a vasodilatory effect, reduces blood pressure and augments expansive remodeling of the uteroplacental vasculature in pregnant rats. In this study, slow-release osmotic pumps were implanted in gravid rats (on day 8) to provide 1 week of PP13 supplementation. Treatment was associated with a reversible blood pressure reduction that returned to normal on day 15. In addition, PP13 caused venous expansion that is larger in the venous branches closer to the placenta. Then, it increased placental and pup weights. Similar administration of a truncated PP13 variant (DelT₂₂₁) that is unable to bind carbohydrates (a rare spontaneous mutation associated with a high frequency of severe early preeclampsia among Blacks in South Africa) produced a hypotensive effect similar to the full-length molecule, but without venous remodeling and increased placental and pup weights. These results indicate the importance of PP13 carbohydrate binding for inducing vascular remodeling and improving reproductive outcome. Future studies are needed to determine whether beneficial effects would be evident in animal models of preeclampsia or in women predisposed to the development of preeclampsia.

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A potential pathophysiological role for galectins and the renin–angiotensin system in preeclampsia

Blois

Dechend

Barrientos

et al. 2014

Cell. Mol. Life Sci.

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This review discusses a potential role of galectins and the renin-angiotensin system (RAS) in the pathophysiology of preeclampsia (PE). Preeclampsia affects between 3 and 5 % of all pregnancies and is a heterogeneous disease, which may be caused by multiple factors. The only cure is the delivery of the placenta, which may result in a premature delivery and baby. Probably due to its heterogeneity, PE studies in human have hitherto only led to the identification of a limited number of factors involved in the pathogenesis of the disease. Animal models, particularly in mice and rats, have been used to gain further insight into the molecular pathology behind PE. In this review, we discuss the picture emerging from human and animal studies pointing to galectins and the RAS being associated with the PE syndrome and affecting a broad range of cellular signaling components. Moreover, we review the epidemiological evidence for PE increasing the risk of future cardiovascular disease later in life.

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Effects of Placental Protein 13 on the Cardiovascular System in Gravid and Non-Gravid Rodents

Cited by 31 publications

References 31 publications

The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant

The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant

Placental Protein 13 Administration to Pregnant Rats Lowers Blood Pressure and Augments Fetal Growth and Venous Remodeling

A potential pathophysiological role for galectins and the renin–angiotensin system in preeclampsia

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