Galectin 13 (PP13) Facilitates Remodeling and Structural Stabilization of Maternal Vessels during Pregnancy.

Galectins regulate cell growth, proliferation, differentiation, apoptosis, signal transduction, mRNA splicing, and interactions with the extracellular matrix. Here we focus on the galectins in the reproductive system, particularly on a group of six galectins that first appears in anthropoid primates in conjunction with the evolution of highly invasive placentation and long gestation. Of these six, placental protein 13 (PP13, galectin 13) interacts with glycoproteins and glycolipids to enable successful pregnancy. PP13 is related to the development of a major obstetric syndrome, preeclampsia, a life-threatening complication of pregnancy which affects ten million pregnant women globally. Preeclampsia is characterized by hypertension, proteinuria, and organ failure, and is often accompanied by fetal loss and major newborn disabilities. PP13 facilitates the expansion of uterine arteries and veins during pregnancy in an endothelial cell-dependent manner, via the eNOS and prostaglandin signaling pathways. PP13 acts through its carbohydrate recognition domain that binds to sugar residues of extracellular and connective tissue molecules, thus inducing structural stabilization of vessel expansion. Further, decidual PP13 aggregates may serve as a decoy that induces white blood cell apoptosis, contributing to the mother's immune tolerance to pregnancy. Lower first trimester PP13 level is one of the biomarkers to predict the subsequent risk to develop preeclampsia, while its molecular mutations/polymorphisms that are associated with reduced PP13 expression are accompanied by higher rates of preeclampsia We propose a targeted PP13 replenishing therapy to fight preeclampsia in carriers of these mutations.

Placental protein 13 (PP13) stimulates rat uterine vessels after slow subcutaneous administration.

INTRODUCTION: Reduced concentrations of placental protein 13 (PP13) during the first trimester of human pregnancy are associated with elevated risk for the subsequent development of preeclampsia, which is one of the deadliest obstetrical complications of pregnancy. Previous studies by our group have shown that PP13 lowers blood pressure in pregnant rats, increases the size and weight of pups and placentas, and induces vasodilation of resistance arteries through endothelial signaling pathways involving endothelial nitric oxid synthase and prostaglandin. METHODS: In the present study, the effect of PP13 was investigated in nonpregnant female Sprague Dawley rats (n=27). Osmotic pumps were surgically implanted subcutaneously that released a constant dose of PP13 or saline over 7 days. Most animals were sacrificed 6 days after the end of PP13 release (on day 13), while some were sacrificed immediately at the end of day 7 (the last PP13 release day), to compare the short- and long-term impact of PP13 on vessels' growth and size. RESULTS: The uterine vessels were significantly expanded in the group exposed to recombinant PP13 (rPP13) compared to the control (saline) group. Both veins and arteries were significantly expanded by rPP13 with a more pronounced effect after 13 days compared to the corresponding vessels after 7 days. Furthermore, the long-term effect of treatment by rPP13 was more pronounced in the veins compared to the corresponding arteries. The effect of a PP13 variant with a histidine-tag (His-PP13) remained the same between 7 and 13 days. CONCLUSION: In conclusion, PP13 might play a key role in the expansive remodeling of the uterine vessels, reflecting what would happen if the rat was pregnant, preparing the uterine vascu-lature for the increase in uteroplacental blood flow, which is necessary for normal pregnancy. We suggest that PP13 could act by NO signaling pathways, a hypothesis that requires future study.

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits.

INTRODUCTION: Human placental protein 13 (PP13) is a galectin predominantly expressed by the placenta. Low serum concentrations of PP13 in early pregnancy indicate a higher risk of developing preeclampsia. METHODS: The pharmacokinetic disposition and bioavailability of PP13 were determined by single intravenous and subcutaneous administration to 12 healthy New Zealand White rabbits. The serum pharmacokinetic values were determined by enzyme-linked immunosorbent assay, and are best described by a two-compartment model. RESULTS: Both volume of distribution and the area under the curve were dose dependent for the intravenous group (p<0.01). PP13 elimination half-life was also found to be different between the groups (p<0.01). The bioavailability of PP13 following subcutaneous administration was found to be 57%. CONCLUSION: This study shows that the concentration of total PP13 released into the maternal circulation during pregnancy might be much higher than previously estimated.

Placental protein 13 (PP13)-induced vasodilation of resistance arteries from pregnant and nonpregnant rats occurs via endothelial-signaling pathways.

Placental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects on isolated uterine arteries from nonpregnant and mid-pregnant rats. Vessels were isolated, cannulated, and pressurized to 50 mmHg within an arteriograph, preconstricted and exposed to increasing PP13 concentrations (10-13-10-8 M). PP13 elicited 38-50% arterial vasodilation with half-maximum response (EC50) = 1 pM. The relaxation was mediated by activating the endothelial-signaling pathways of prostaglandin and nitric oxide (NO). Accordingly, these results encourage evaluation of PP13 as a possible therapy for gestational diseases characterized by insufficient uteroplacental blood flow and/or maternal hypertension.