An autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through deregulated VEGFA, NOS1, and CTNNB1

The uterus undergoes vascular changes during the reproductive cycle and pregnancy. Steroid hormone deprivation induces macroautophagy/autophagy in major uterine cell types. Herein, we explored the functions of uterine autophagy using theAmhr2-Cre-drivenatg7deletion model. Deletion ofAtg7was confirmed by functional deficit of autophagy in uterine stromal, myometrial, and vascular smooth muscle cells, but not in endothelial cells.atg7(d/d)uteri exhibited enhanced stromal edema accompanied by dilation of blood vessels. Ovariectomizedatg7(d/d)uteri showed decreased expression of endothelial junction-related proteins, such as CTNNB1/beta-catenin, with increased vascular permeability, and increased expression of VEGFA and NOS1. Nitric oxide (NO) was shown to mediate VEGFA-induced vascular permeability by targeting CTNNB1. NO involvement in maintaining endothelial junctional stability inatg7(d/d)uteri was confirmed by the reduction in extravasation following treatment with a NOS inhibitor. We also showed thatatg7(d/d)uterine phenotype improved the fetal weight:placental weight ratio, which is one of the indicators of assessing the status of preeclampsia. We showed that autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through the deregulation of VEGFA, NOS1, and CTNNB1.

Automated summary

The study revealed that the deficit of autophagy in the uterine vessel microenvironment provokes hyperpermeability through the deregulation of VEGFA, NOS1, and CTNNB1, affecting the vascular stability and function.