CD81 restricts decidual IGF2-mediated smooth muscle cell dedifferentiation during spiral artery remodeling in...

Preeclampsia (PE) is a pregnancy-specific complication characterized by defective spiral artery remodeling, notably due to the abnormal retention of differentiated vascular smooth muscle cells (VSMCs). Although elevated CD81 levels in the placenta and maternal circulation contribute to this impairment, the definite mechanisms remain elusive. This study aimed to investigate how CD81 overexpression in extravillous trophoblasts (EVTs) contributes to defective VSMC dedifferentiation within uterine spiral arteries, as well as the involved molecular mechanisms.

Placental basal plates from severe preeclampsia (sPE) patients and non-PE controls were immunostained for CD81 and VSMC markers. A placental restricted CD81 overexpression mouse model was constructed to evaluate PE-like phenotype and placental pathology. Primary decidual stromal cells (DSCs) and natural killer (dNK) cells were applied to investigate how CD81-overexpressing EVTs interact with them to suppress VSMC dedifferentiation. Additionally, antagonistic and rescue experiments were conducted to identify the function of the key molecules involved.

The proportion of retained differentiated VSMCs in spiral arteries was significantly higher in sPE patients than in normal pregnancies, and was positively correlated with CD81 expression on EVTs. Similarly, pregnant mice with placental restricted CD81 overexpression exhibited PE-like phenotype and showed persistent VSMC retention in spiral arteries. In vitro, conditioned medium (CM) from DSCs pretreated with medium from CD81-overexpressing EVTs increased the expression of differentiated VSMC markers, which was associated with reduced insulin-like growth factor 2 (IGF2) levels in DSCs. Notably, exogenous IGF2 supplementation reversed this effect.

CD81 upregulation on EVTs prevents VSMC dedifferentiation through a DSC-dependent mechanism. This study represents a pioneering effort to reveal the crucial role of interplay between EVTs, DSCs, and VSMCs in facilitating VSMC dedifferentiation, thereby enabling the completion of spiral artery remodeling.