Genetic Deletion of Placenta Growth Factor in Mice Alters Uterine NK Cells

Abstract

Placenta growth factor (PlGF; formerly PGF), a vascular endothelial growth factor gene family member, is expressed in human implantation sites by maternal uterine NK (uNK) and fetal trophoblast cells. Lower than normal concentrations of blood and urinary PlGF have been associated with impending onset of pre-eclampsia, a hypertensive disease of late human gestation characterized by limited intravascular trophoblast invasion. In pregnant rodents, delivery of the PlGF antagonist sFlt-1 or S-endoglin induces pre-eclampsia-like lesions. Mice genetically deleted in PlGF reproduce, but neither their implantation sites nor their uNK cell development are described. We combined real-time PCR of endometrium from nonpregnant and gestation day (gd)6–18 C57BL6/J (B6) mice with immunohistology to analyze PlGF expression in normal mouse pregnancy. To estimate the significance of uNK cell-derived PlGF, PlGF message was quantified in mesometrial decidua from pregnant alymphoid Rag2 null/common γ chain null mice and in laser capture-microdissected B6 uNK cells. Histopathologic consequences from PlGF deletion were also characterized in the implantation sites from PlGF null mice. In B6, decidual PlGF expression rose between gd8–16. uNK cells were among several types of cells transcribing PlGF in decidualized endometrium. Immature uNK cells, defined by their low numbers of cytoplasmic granules, were the uNK cells displaying the greatest number of transcripts. PlGF deletion promoted the early differentiation high numbers of binucleate uNK cells (gd8) but had no other significant, morphometrically detectable impact on implantation sites. Thus, in mice, PlGF plays an important role in successful uNK cell proliferation and/or differentiation.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…However, high sFLT1 levels in the placenta likely neutralize local PlGF (Kendall et al 1996;Cindrova-Davies et al 2011;Furuya et al 2011). PlGF also regulates the maturation of uterine natural killer cells in the endometrium needed for trophoblast invasion (Tayade et al 2007). Overall, although PlGF is expressed in development, its role is largely redundant.…”

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

“…Mouse uNK cells promote uterine lumen closure, angiogenesis, the rate of early fetal development and they initiate spiral artery remodelling. [13][14][15] In contrast to human uNK cells, mouse uNK cells appear in the uterus after implantation rather than following the menstrual cycle surge luteinizing hormone. 16,17 Although mouse trophoblast cells express MHC molecules, 18 mouse uNK cells may have only an indirect influence on trophoblast invasion.…”

Reproductive Performance in Diabetes Mice with a Special Reference to Uterine Natural Killer Cells and Placental Growth Factor

“…Prominent production of PlGF by trophoblast and the presence of Flt-1 receptors on trophoblast suggest that PlGF may act in an autocrine manner to modulate the trophoblast differentiation [23]. The uNK cells can also produce PlGF [3,4,24,25], suggesting that uNK cells may support the differentiation of endothelial cells together with VEGF. The present study also showed that PlGF protein did not change under diabetes condition, although PlGF mRNA expression was decreased.…”

“…For quantification of PlGF expression, the SYBR Green PCR Master Mix (Applied Biosystems, U.S.A.) was used. PlGF primers are designed as forward (5'-TGCTGGTCATGAAGCTGTTC-3') and reverse (5'-GGACACAGGACGGACTGAAT-3') [24]. Data were quantified using StepOne Software for StepOne and StepOnePlus Real-Time PCR system (Applied Biosystem, U.S.A.).…”