한빛사 논문
Lee, B.a, Shin, H.a, Oh, J.-E.b, Park, J.a, Park, M.c, Yang, S.C.c, Jun, J.-H.d,e, Hong, S.-H.f, Song, H.c,*, Lim, H.J.a,b,*
aDepartment of Biomedical Science & Technology, Konkuk University, Seoul, South Korea
bDepartment of Veterinary Medicine, Konkuk University, Seoul, South Korea
cDepartment of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, South Korea
dDepartment of Biomedical Laboratory Science, Eulji University, Seongnam, Gyeonggi-do, South Korea
eDepartment of Senior Healthcare, BK21 Plus Program, Eulji Medi-Bio Research Institute, Graduate School, Eulji University, Daejeon, South Korea
fDepartment of Internal Medicine, School of Medicine, Kangwon National University, Kangwon-do, Chuncheon, South Korea
*Corresponding author
Abstract
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 the Amhr2-Cre-driven atg7 deletion model. Deletion of Atg7 was confirmed by functional deficit of autophagy in uterine stromal, myometrial, and vascular smooth muscle cells, but not in endothelial cells. atg7d/d uteri exhibited enhanced stromal edema accompanied by dilation of blood vessels. Ovariectomized atg7d/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 in atg7d/d uteri was confirmed by the reduction in extravasation following treatment with a NOS inhibitor. We also showed that atg7d/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.
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