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Elevated circulating and placental SPINT2 is associated with placental dysfunction

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posted on 2021-08-06, 04:18 authored by CN Murphy, SP Walker, TM Macdonald, E Keenan, NJ Hannan, Mary WlodekMary Wlodek, J Myers, JF Briffa, Tania StasisTania Stasis, A Roddy Mitchell, CA Whigham, P Cannon, TV Nguyen, M Kandel, N Pritchard, S Tong, TJ Kaitu’u-lino
Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24–34 weeks’ (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-tri-mester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.


Funding for this work was provided by the National Health and Medical Research Council (#1065854, #1183854, #116071, #2000732), National Health and Medical Research Council Fellowships to TKL (#1159261), NJH (#1146128), ST (#1136418). The funders played no role in study design or analysis.


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International Journal of Molecular Sciences





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