Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

SPINT2 expression in pregnancies complicated by placental insufficiency (#112)

Ciara Murphy 1 , Susan P Walker 1 , Teresa M MacDonald 1 , Emerson Keenan 1 , Natalie J Hannan 1 , Mary E Wlodek 2 , Jenny Myers 3 , Jessica F Briffa 2 , Tania Romano 4 , Ping Cannon 1 , Tuong-Vi Nguyen 1 , Manju Kandel 1 , Natasha Pritchard 1 , Cathy Cluver 5 , Stephen Tong 1 , Tu'uhevaha J Kaitu'u-Lino 1
  1. Obstetrics & Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC, Australia
  2. Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia
  3. Manchester Academic Health Science Centre, St Mary's Hospital, University of Manchester, Manchester, UK
  4. Physiology, Anatomy & Microbiology, La Trobe University, Bundoora, VIC, Australia
  5. Tygerberg Hospital, University of Stellenbosch, Cape Town, South Africa

Poor placental implantation can lead to preeclampsia and/or delivery of a small for gestational age (SGA) fetus. Diagnostic tools to predict placental insufficiency have limited accuracy. We recently reported circulating SPINT11 to have the strongest association with placental insufficiency of any protein. SPINT1 is a protease inhibitor expressed on the surface of trophoblasts and secreted into the maternal circulation. Here we sought to investigate SPINT2, a structurally and functionally related protein of SPINT1.

We measured circulating SPINT2 in several large cohorts: 1) a prospective case-cohort collection at 36 weeks’ gestation (n=326, cohort 1 from Australia); 2) prospective 24-34 weeks’ gestation samples (n=132, cohort 2 from UK); and, 3) patients with established preterm preeclampsia (cohort 3, Australia). Plasma SPINT2 was elevated prior to diagnosis at 36 weeks’ gestation in women who later developed preeclampsia (p=0.028; cohort 1) or delivered an SGA baby (p=0.002, cohort 1). However, no change was observed in those sampled earlier (24-34 weeks, cohort 2) who later delivered with preeclampsia or SGA. In the cohort with established preeclampsia, placental and circulating SPINT2 was significantly elevated (p=0.025, cohort 3).

We next performed in vitro studies where we assessed the effect of inflammatory cytokines or hypoxia (1% vs 8% O2) on SPINT2 expression in human cytotrophoblast stem cells. We also measured Spint2 mRNA expression in placentas from a rat model of late-gestation (day 18) restricted uteroplacental perfusion (in vivo placental insufficiency/hypoxia model). While inflammatory cytokines did not affect SPINT2 expression, hypoxia significantly increased SPINT2 in cytotrophoblast stem cells and its expression was also significantly elevated (p=0.04) in the placental labyrinth of growth restricted rats.

In conclusion, circulating SPINT2 is increased among those with preeclampsia or SGA, though not earlier than 34 weeks' gestation. Placental SPINT2 expression was also increased in both in vitro and in vivo models of placental hypoxia.