Extracellular matrix induces trophoblast HtrA4 expression: Implications for the pathogenesis of placenta accreta spectrum

Objective

To study whether the upregulation of HtrA4 expression in extravillous trophoblasts and the downregulation of HtrA1 expression in defective deciduae underlined the mechanisms of placenta accreta spectrum (PAS) development.

Methods

Tissue samples from patients undergone cesarean hysterectomy because of postpartum hemorrhage due to PAS (n = 15) or uterine atony (control group; n = 10) were analyzed through immunostainings. The effect of extracellular matrix (ECM) on trophoblast HtrA4 expression, and HtrA4 in the alteration of trophoblast epithelial-to-mesenchymal transition, proliferation, invasion and HtrA1 inhibition were assessed.

Results

ECM molecule collagen I, collagen IV, fibronectin, or laminin were highly expressed in decidua and myometrium. Culturing trophoblasts with these molecules induced HtrA4 expression. HtrA4 upregulated the expression of N-cadherin, vimentin, integrin β1, snail, and matrix metalloproteinase-2 but downregulated that of zonula occludens-1. HtrA4 knockdown inhibited these effects. HtrA4 knockdown or pretreatment with recombinant HtrA1 inhibited HtrA4-induced trophoblast invasion. HtrA4 promoted trophoblast proliferation. Numerous extravillous trophoblasts exhibiting strong HtrA4 expression invaded the myometrium at the villous adherence sites affected by PAS. Relatively few extravillous trophoblasts were observed at the nonadherence sites and in the control specimens; these trophoblasts exhibited weak or no HtrA4 expression. HtrA1 was primarily expressed over the decidua.

Discussion

ECM in decidua and myometrium induced trophoblast HtrA4 expression. Decidual HtrA1 inhibited HtrA4-induced trophoblast invasion. Without the inhibition of HtrA1, HtrA4 expression and invasion was upregulated in the trophoblasts of patients with PAS. The reciprocal effects of HtrA4 and HtrA1 at the maternal-fetal interface may be involved in the pathogenesis of PAS.