Thrombospondin-1 (THBS1) is dysregulated in preeclampsia

Preeclampsia involves endothelial dysfunction and impaired angiogenesis. Thrombospondin-1 (THBS1), a pro-thrombotic and anti-angiogenic glycoprotein, may contribute to preeclampsia pathogenesis. This study investigated the role of THBS1 in preeclampsia.

THBS1 mRNA expression and protein levels were measured in placentas from early-onset preeclampsia (<34 weeks) and gestation-matched controls. Circulating THBS1 was assessed in early-onset preeclampsia and at 36 weeks' gestation preceding diagnosis of preeclampsia at term. THBS1 was examined during human trophoblast stem cell (hTSC) differentiation into syncytiotrophoblast and extravillous trophoblast (EVT) and compared to a public hTSC organoid dataset. THBS1 regulation was assessed in hTSCs exposed to hypoxia and inflammatory cytokines. Investigating the source of circulating THBS1, we induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs) with TNFα and treated them with recombinant THBS1.

THBS1 mRNA (P < 0.0001, n = 78 vs n = 30 controls) and protein (P = 0.0039, n = 43 and n = 21 controls) levels were significantly reduced in early-onset preeclamptic placentas. Contrastingly, circulating THBS1 was elevated in early-onset preeclampsia (P = 0.011, n = 35 vs n = 27 controls) and preceding term preeclampsia diagnosis (P = 0.0025, n = 21 vs n = 184 controls). THBS1 decreased during syncytiotrophoblast (P = 0.0028) and EVT differentiation (P = 0.0008), indicating mainly cytotrophoblast expression. Analysis of a public hTSC organoid dataset confirmed this. Hypoxic (1 % O₂ vs 8 % O₂) and TNFα or IL-6 exposure led to differential expression and secretion of THBS1. We observed no changes in THBS1 with induced endothelial dysfunction. Recombinant THBS1 had no effect on endothelial dysfunction.

THBS1 is dysregulated in preeclampsia and may be regulated by hypoxic stimuli. These findings support THBS1 as a potential mediator in preeclampsia pathogenesis.