Mesenchymal-specific deletion of Atg7 in the mouse uterus leads to aberrant vascular response


 

Mesenchymal-specific deletion of Atg7 in the mouse uterus leads to aberrant vascular response
 
Hyejin Shin1,2, Bora Lee1, Jaekyoung Park1, Mira Park2, Haengseok Song2, Hyunjung Jade Lim1
1Konkuk University, Seoul, Korea; 2CHA University, Seongnam, Korea
      
We previously showed that hormone deprivation in the mouse uterus enhances autophagy in all major cell types of the uterus, whereas estrogen (E) or progesterone (P) suppresses such induction. To explore physiological function of autophagy in the uterus, we produced the uterine cell type-specific Atg7 deletion mouse model (Atg7d/d) by crossing Atg7flox/flox (Atg7f/f) mice and Anti-Müllerian hormone type 2 receptor (Amhr2)-cre mice (Amhr2cre). We confirmed successful deletion of Atg7 gene in the uterine stromal and myometrial cells, as well as in the vascular smooth muscle cells, which was evidenced by massive accumulation of p62 in these cells of ovariectomized (OVX) Atg7d/d mice. While Atg7d/d female mice gave birth normally, enhanced stromal edema accompanying vessel dilation was notable in the uterus. The number of small vessels in the subepithelial stromal regions was comparable between control and Atg7d/d uteri, but blood vessels and lymphatic vessels were much dilated in Atg7d/d uteri, suggesting that an increased vascular permeability may cause such dilation. The Miles assay using uterine tissues showed a significant increase in the vascular permeability, which is in accordance with decreased expression of Claudin-5 in Atg7d/d uteri. FACS analyses revealed that CD146-positive cells increased in Atg7d/d uterine stromal cell preparations, suggesting a potential hypertrophy of CD146-positive vascular mural cells and other cells of mesenchymal origin. These results suggest that an autophagic deficit in the vascular mural cells leads to increased vascular permeability and enhanced stromal edema in the uterus. Aberrant expression of several extracellular matrix mRNAs in Atg7d/d uteri may indicate decreased flexibility of uterine vessels. The results show that autophagy in vascular mural cells is required for the maintenance of vascular permeability in the uterus.
 
This research was supported in part by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C1133) and by a grant from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A2B4002932).
 

 
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