UNK cell-derived TGF-β1 regulates the long noncoding RNA MEG3 to control vascular smooth muscle cell migration and apoptosis in spiral artery remodeling.

Abstract

Successful pregnancy depends on correct spiral artery (SpA) remodeling, and thus, on normal patterns of the vascular smooth muscle cell (VSMC) apoptosis and migration. Uterine natural killer (uNK) cells-derived transforming growth factor β1 (TGF-β1) is known to mediate the separation of VSMC layers via as yet unknown mechanisms. Likewise, the long noncoding RNA maternally expressed gene 3 (MEG3) is a tumor suppressor that has been shown to regulate cancer cell apoptosis and migration; however, its role in VSMC loss is unclear. Thus, the aim of the present study was to assess the effects of uNK-derived TGF-β1 and MEG3 on VSMC function during SpA. Analyses were conducted to assess the effects of downregulating MEG3 expression, and/or administering treatments to increase or block TGF-β1 signaling on VSMC survival and behavior. The results of these analyses showed that treating the VSMC with uNK cell-derived supernatant or recombinant human TGF-β1 promoted MEG3 and matrix metalloprotease 2 expression and VSMC apoptosis and migration, and suppressed VSMC proliferation. Conversely, MEG3 silencing promoted VSMC proliferation and inhibited VSMC apoptosis and migration. Notably, TGF-β1 signaling induction had no significant effect on the proliferation, apoptosis, nor migration of the MEG3-silenced VSMC. Together, these findings suggest that MEG3 is regulated by uNK-derived TGF-β1, and itself mediates VSMC apoptosis and migration; thus, it may be an important positive regulator of VSMCs separation during maternal SpA remodeling.