Galectin-3 deficiency in pregnancy increases the risk of fetal growth restriction (FGR) via placental insufficiency

Abstract

Fetal growth restriction (FGR) is the most common pregnancy complication in developed countries. Pregnancies affected by FGR, frequently concur with complications and high risk of neonatal morbidity and mortality. To date, no approved treatment is available for pregnant women affected with FGR. The objective of this study was to investigate the contribution of galectin-3 (gal-3), a β-galactoside binding protein involved in pregnancy, placental function and fetal growth. We demonstrated that lack of gal-3 during mouse pregnancy leads to placental dysfunction and drives FGR in the absence of a maternal preeclampsia syndrome. Analysis of gal-3 deficient dams revealed placental inflammation and malperfusion, as well as uterine natural killer cell infiltration with aberrant activation. Our results also show that FGR is associated with a failure to increase maternal circulating gal-3 levels during the second and third trimester in human pregnancies. Placentas from human pregnancies affected by FGR displayed lower gal-3 expression, which correlated with placental dysfunction. These data highlight the importance of gal-3 in the promotion of proper placental function, as its absence leads to placental disease and subsequent FGR.

Galectin-Levels Are Elevated in Infants Born Preterm Due to Amniotic Infection and Rapidly Decline in the Neonatal Period

“…Maternal gal-9 circulating levels are elevated at the time of parturition but returning to non-pregnant levels during postpartum ( 8 ). Consistent with this, the chimera lectin, gal-3 is highly expressed at the decidual and placental compartment and after parturition its expression dramatically decreased as the implantations sites resorbed ( 9 , 10 ). Although galectin interactions during gestation are well characterized, the potential outcome of these interactions in the context of preterm birth are poorly defined.…”

“…In comparison with the increasing number of studies focusing on the galectin profile in the maternal circulation, information on the systemic variations of galectin levels in the fetus/newborn is very scarce to date. Current evidence indicates that uneventful pregnancy is associated with a steady increase of maternal circulating levels of the three galectins investigated in this study from the first to the third trimester ( 10 , 22 , 23 ), suggesting that the kinetics of galectin secretion may be subject to regulation by different sets of signals operating in the maternal and fetal compartment. Thus, one possibility that requires further investigation is that galectins function to shape innate immunity until the newborn achieves full immune competence and that the very same signals that drive fetal maturation and trigger parturition are also involved in the regulation of the systemic galectin signature as a mechanism to prepare the fetus for the challenges of extrauterine life.…”

Insight into the Key Points of Preeclampsia Pathophysiology: Uterine Artery Remodeling and the Role of MicroRNAs

“…Ruikar et al revealed the increased expression of annexin A1 and galectin-3 in placental tissue of preeclamptic women, suggesting the role of these proteins in PE pathophysiology by participating in a systemic inflammatory response [ 49 ]. Furthermore, the development of FGR is accompanied by an altered pattern of circulating galectin-3 levels and galectin-3 deficiency in mouse pregnancy leading to placental insufficiency and the subsequent development of FGR [ 50 ]. It is well established that galectin-3 stimulates angiogenesis through the VEGF receptor dependent pathway and may also inhibit apoptosis in different types of cells.…”

Galectina-3 controla a proliferação intracelular de Toxoplasma gondii em células trofoblásticas humanas (linhagem BeWo)

“…Diante do exposto, de modo geral, durante infecção por patógenos intracelulares, como T. gondii, Gal-3 tem importante papel pró-inflamatório, na ativação de células da defesa inata e no controle da proliferação intracelular do parasito (BERNARDES et al, 2006;ALVES et al, 2013;LIU et al, 2018). Na interface materno-fetal, Gal-3 está presente em células trofoblásticas e contribui para o desenvolvimento da gestação (YANG et al, 2011;HUTTER et al, 2016;FREITAG et al, 2020). Nesse sentido, nossos resultados mostraram pela primeira vez que Gal-3 modula eventos de adesão, invasão e proliferação, bem como perfil de citocinas secretadas em células trofoblásticas da linhagem BeWo durante a infecção por T. gondii e, portanto, influencia no controle do parasitismo (Figura 6).…”

“…Gal-3 tem um papel importante na interação do embrião com o endométrio durante a implantação já que está aumentada na fase secretora do ciclo menstrual por influência hormonal, além disso, sua expressão nas células endometriais é regulada por HCG (gonadotrofina coriônica humana (UNVERDORBEN et al, 2016;MIYAUCHI et al, 2018). A diminuição da expressão de Gal-3 no endométrio está associada a distúrbios gestacionais, por exemplo, a restrição do crescimento fetal por insuficiência placentária (FREITAG et al, 2020).…”