Angiopoietin-2 regulates the phenotypic switch of vascular smooth muscle cells.

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.