Proteomic analysis reveals angiogenesis-related plasma proteins associated with pre-eclampsia in SLE

Delivery of a small for gestational age (SGA) infant is a common pregnancy complication among women with SLE. Although disease activity and autoantibodies such as anti-Smith and anti-ribonucleoprotein associate with SGA, underlying pathological mechanisms remain unclear and reliable predictors are lacking. To address this, we applied a proteomic approach to identify proteins associated with SGA in SLE.

Plasma samples were collected repeatedly during pregnancy, at delivery and from placental intervillous blood in women with SLE (n=83) and healthy controls (n=67) enrolled in the prospective SLE-Placenta study. Postpartum samples (≥6 months) from a subset of women with SLE (n=19) served as non-pregnant controls. Mass spectrometry was performed on a discovery cohort comprising six healthy uncomplicated pregnancies, eight uncomplicated SLE pregnancies and eight SLE pregnancies complicated by SGA (SLE-SGA). Differential protein abundance analysis was performed in R. Candidate proteins were quantified by ELISA in the full cohort.

Discovery proteomics identified four proteins with increased abundance in SLE-SGA compared with uncomplicated SLE pregnancies: endostatin (P _adj =0.0003), angiogenin (P _adj =0.03), insulin-like growth factor-binding protein 5 (P _adj =0.03) and complement factor H-related protein 5 (P _adj =0.004). In the full cohort, ELISA quantification did not confirm increased levels of these proteins in SLE-SGA but suggested elevated levels of the angiogenesis-related proteins endostatin and angiogenin in women with SLE who later developed pre-eclampsia. Endostatin levels were consistently higher in SLE compared with controls across all trimesters (p≤0.0001). Endostatin, but not angiogenin, was enriched in placental blood.

Our study did not validate the differentially abundant proteins as markers for SLE-SGA but suggested a link between the antiangiogenic and proangiogenic proteins, endostatin and angiogenin, respectively, and pre-eclampsia in SLE. Given the consistent elevation of endostatin throughout pregnancy in SLE compared with controls, its potential effects on placental development in SLE warrant further investigation.