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

Abstract

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.

Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age

“…PP13 was implicated in several functions of placental development, including immune tolerance to the paternal genes of the migrating trophoblasts [16, 23] as well as blood pressure and uteroplacental vasculature control [25]. Therefore, knowledge of polymorphisms in the promoter region for this gene might facilitate our understanding of its potential role in regulating the normal progress of pregnancy.…”

“…The polypeptides were subsequently purified as recombinant proteins yielding DelT 221 as a shorter variant compared to the wild type due to a premature stop codon in the open reading frame. When the wild type and truncated PP13 were applied, each was capable of reducing the blood pressure in gravid rats, and this effect lasted for the entire period of PP13 delivery from slow-releasing inter-peritoneal pumps [25]. However, unlike the wild-type, the truncated PP13 failed to cause expansion of the utero-placental vasculature and could not increase placental size and pup weight [25, 37].…”

“…When the wild type and truncated PP13 were applied, each was capable of reducing the blood pressure in gravid rats, and this effect lasted for the entire period of PP13 delivery from slow-releasing inter-peritoneal pumps [25]. However, unlike the wild-type, the truncated PP13 failed to cause expansion of the utero-placental vasculature and could not increase placental size and pup weight [25, 37]. These findings emphasize the role of the sugar-binding residues of the PP13 molecule that are partially missing in the truncated variant as was demonstrated previously [16, 34, 36].…”

“…This set of evidence links PP13 to early and intermediate PE. The A/A genotype variation of reduced PP13 expression might be correlated with the hypotension induced by PP13, which occurs regardless of the molecular part responsible for immune tolerance [25]. Thus, PP13 impacts on main maternal artery expansion to enable the increase in cardiac output to coop with the increased burden of pregnancy and the systemic effect of PP13 on vasodilation, and the endothelial layer might be relevant to its importance in endothelial insufficiency in term PE.…”

“…PP13 is implicated in placentation [16, 20, 21], and is involved in inflammation and immune defense required for trophoblast invasion during uterine artery remodeling in early pregnancy [16, 21–24]. PP13 decreases blood pressure, causes blood vessel dilation and diameter expansion, and stimulates the development of larger placenta and pups in pregnant rats [25]. Lower LGALS13 expression [26, 27] and reduced serum PP13 levels [22] are correlated with high risk to develop PE in the first trimester.…”