Galectin signature in pregnancy: defining the contribution of galectin-3
Final Report Abstract
Galectins, a family of soluble glycan-binding proteins are currently emerging as powerful modulators of pregnancy associated processes including proper placental development. Within the galectin family, the chimera-type galectin-3 (gal-3, encoded by Lgals3 gene) is highly expressed at the feto-maternal interface. Gal-3 knock down in mouse endometrium results in substantially less implanted embryos, and dysregulation of gal-3 is associated with several obstetric complications (preeclampsia (PE), hemolysis elevated liver enzymes and low platelets (HELLP) syndrome, small-for-gestational age and gestational trophoblastic disease). At present, the impact of dysregulated gal-3 expression in placental development and pregnancy outcome has not been addressed. In this project, we found that gal-3 loss of function during gestation altered the decidual compartment favoring a pro-inflammatory milieu, reducing stroma cell proliferation and decidual angiogenic response which was accompanied by a decrease in progesterone (Prg) in maternal circulation. In the placental compartment, lack of gal-3 compromised placental vascularization and perfusion resulting in placental insufficiency and the subsequent development of asymmetric FGR in mice. Using various human trophoblast cell lines, we showed that gal-3 influences the invasive properties and tube formation capacities of the cells, revealing the importance of gal-3 in trophoblast function associated with placental vascularization. We also showed that placental gal-3 expression is down-regulated in human pregnancies complicated with FGR, demonstrating that gal-3 also plays a role in human FGR pathology. Finally, using reciprocal matings we identified that gal-3 within the maternal compartment is required for proper placental development and fetal growth. Our findings identify gal-3 as a key component of the molecular program of decidua, placenta development and offspring health, as well as a potential target for future strategies aimed at minimizing adverse outcomes in pregnancies at high risk for fetal growth restriction. Additionally, we analyzed the expression of gal‐3 during normal and pathological pregnancies to gain insight into its possible function during human gestation. We showed that normal progression of pregnancy is associated with an increase in systemic gal‐3 levels. Furthermore, maternal circulating gal‐3 decreased upon onset of gestational diabetes mellitus (GDM). These observations provide prospects for the development of complementary diagnostic tools that target gal‐3 in routine gynecologic analysis. In summary, our project reveals dysregulated gal-3 expression in human pregnancies affected by impaired fetal growth are consistent with the role played by this lectin in pregnancy orchestration as demonstrated in our mouse studies. Particularly, the fact that besides sharing a common placental histopathology, FGR and PE placentas differed in their pattern of regulation of gal-3 expression is of great importance. Our clinical and experimental findings demonstrated that gal-3 loss of function is not sufficient to provoke a maternal PE-like syndrome in mice, and women with both early and late-onset PE showed no alterations in gal-3 expression. Because gal-1 and gal-3 are the most prominent galectins associated with critical processes in early gestation, we hypothesize that unique properties exerted by gal-3 in supporting placental development, fetal growth, and pregnancy cannot be substituted by gal-1. Our study is clinically relevant and reinforces the concept that unique functional properties in support of healthy pregnancy are specific to each of the different members of the placental galectin network.
Publications
- A potential pathophysiological role for galectins and the reninangiotensin system in preeclampsia. Cell Mol Life Sci. 2015 Jan;72(1):39-50
Blois SM, Dechend R, Barrientos G, Staff AC
(See online at https://doi.org/10.1007/s00018-014-1713-1) - Galectins in angiogenesis: consequences for gestation. J Reprod Immunol. 2015 Apr;108:33-41
Blois SM, Conrad ML, Freitag N, Barrientos G
(See online at https://doi.org/10.1016/j.jri.2014.12.001) - Differential Spatiotemporal Patterns of Galectin Expression are a Hallmark of Endotheliochorial Placentation. Am J Reprod Immunol. 2016 Mar;75(3):317-25
Conrad ML, Freitag N, Diessler ME, Hernandez R, Barrientos G, Rose M, Casas LA, Barbeito CG, Blois SM
(See online at https://doi.org/10.1111/aji.12452) - Evidence for Differential Glycosylation of Trophoblast Cell Types. Mol Cell Proteomics. 2016 Jun;15(6):1857-66
Chen Q, Pang PC, Cohen ME, Longtine MS, Schust DJ, Haslam SM, Blois SM, Dell A, Clark GF
(See online at https://doi.org/10.1074/mcp.M115.055798) - Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins. Front Immunol. 2019 May 29;10:1166
Blois SM, Dveksler G, Vasta GR, Freitag N, Blanchard V, Barrientos G
(See online at https://doi.org/10.3389/fimmu.2019.01166) - Galectin-3 deficiency in pregnancy increases the risk of fetal growth restriction (FGR) via placental insufficiency. Cell Death Dis. 2020 Jul 23;11(7):560
Freitag N, Tirado-Gonzalez I, Barrientos G, Powell KL, Boehm-Sturm P, Koch SP, Hecher K, Staff AC, Arck PC, Diemert A, Blois SM
(See online at https://doi.org/10.1038/s41419-020-02791-5) - Role of galectin-glycan circuits in reproduction: from healthy pregnancy to preterm birth (PTB). Semin Immunopathol. 2020 Aug;42(4):469-486
Blois SM, Verlohren S, Wu G, Clark G, Dell A, Haslam SM, Barrientos G
(See online at https://doi.org/10.1007/s00281-020-00801-4) - The chimera-type galectin-3 is a positive modulator of trophoblast functions with dysregulated expression in gestational diabetes mellitus. Am J Reprod Immunol. 2020 Jul 21:e13311
Freitag N, Tirado-González I, Barrientos G, Cohen M, Daher S, Goldman-Wohl D, Mincheva-Nilsson L, John CM, Jeschke U, Blois SM
(See online at https://doi.org/10.1111/aji.13311)
