Balanced levels of nerve growth factor are required for normal pregnancy progression

Abstract

Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of he decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the stablishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, n this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further oosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through ecruitment of NGF-expressing immune cells, increased decidual innervation with substance P+nerve fibres and a Th1 cytokine shift. imilarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions ssociated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the odels, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development.We further demonstrated hat spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. hus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed ay result in fetal rejection due to exacerbated inflammation.