Angiopoietin‐2 regulates the phenotypic switch of vascular smooth muscle cells

Abstract During uterine spiral artery remodeling, vascular smooth muscle cells (VSMCs) become disorganized and undergo phenotypic switching from a contractile to a more synthetic phenotype. We have previously reported that uterine natural killer cells induce this VSMC phenotypic switching by secreting angiopoietin‐2 (Ang‐2). Here, we identified the specific mechanisms by which Ang‐2 plays a role in this phenomenon. VSMCs isolated from human umbilical arteries were used as an in vitro model to investigate the role of Ang‐2 in phenotypic switching. Human decidua tissue from preeclamptic and control pregnancies was collected to compare the expression levels of related proteins. Ang‐2 induced a more synthetic phenotype in VSMCs as evidenced by decreased contractile marker expression, increased proliferation and migration, and an altered cytoskeleton. VSMC expressed integrin β6 interacted directly with Ang‐2 and induced phosphorylation of FAK (S910 and Y397), AKT (S473), and mTOR (S2448). Knockdown of FAK recovered the calponin loss induced by Ang‐2 and resulted in lower EZH2 abundance. Inhibition of FAK and EZH2 both attenuated Ang‐2‐induced inhibition of the LC3 II/LC3 I ratio and ATG7 expression, and proliferation. Lipid peroxidation inhibition by ferrostatin‐1 or the IL‐8 receptor antagonist navarixin inhibited the Ang‐2‐induced migration. IL‐8 secretion was significantly lower with lipid peroxidation inhibition. In preeclamptic decidua, there were more unremodeled spiral arteries, and the abundance of Ang‐2 was dysregulated. Ang‐2 dysregulation may disrupt spiral artery remodeling and contribute to preeclampsia. Ang‐2 may be a novel therapeutic target for the treatment of pregnancy complications affected by incomplete spiral artery remodeling.