AUTHOR=Namiguchi Kenji , Sakaue Tomohisa , Okazaki Mikio , Kanno Kaho , Komoda Yuhei , Shikata Fumiaki , Kurata Mie , Ota Noritaka , Kubota Yoshiaki , Kurobe Hirotsugu , Nishimura Takashi , Masumoto Junya , Higashiyama Shigeki , Izutani Hironori 

TITLE=Unique Angiogenesis From Cardiac Arterioles During Pericardial Adhesion Formation

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.761591

DOI=10.3389/fcvm.2021.761591

ISSN=2297-055X

ABSTRACT=Objectives: The molecular mechanisms underlying post-operative pericardial adhesions remain poorly understood. To unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis.
Methods and Results: Using a previously established murine model, we visualized cell-based tissue dynamics during pericardial adhesion using histological evaluations. To determine the molecular mechanism, RNA-seq was performed. Administrations of chemical inhibitors were conducted to confirm the molecular mechanism required for adhesion formation. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analysis showed that arterioles excessively sprouted from pericardial tissues in mice as well as in humans. The combination of RNA-seq and histological analyses revealed that hyperproliferative endothelial and smooth muscle cells with dedifferentiation appeared in cytokine-exposed sprouting vessels and adhesion tissues, but not in quiescent vessels in the heart. SMAD2/3 and ERK activation was observed in sprouting vessels. The simultaneous abrogation of SMAD2/3, PI3K, and MMP9 signaling showed a significant decrease in angiogenic sprouting, followed by adhesion formation. Our data strongly suggest that vascular smooth muscle cells were dedifferentiated from the contractile to the synthetic phenotype in heart tissue, and matrix metalloproteinase-dependent tissue remodeling and TGF-β signaling activation might contribute to fibrosis in the pericardial cavity.
Conclusions: Our findings provide new insights in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues.