Unique Angiogenesis From Cardiac Arterioles During Pericardial Adhesion Formation

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

doi:10.3389/fcvm.2021.761591

Unique Angiogenesis From Cardiac Arterioles During Pericardial Adhesion Formation

Front Cardiovasc Med. 2022 Feb 3:8:761591. doi: 10.3389/fcvm.2021.761591. eCollection 2021.

Authors

Kenji Namiguchi¹, Tomohisa Sakaue^{1

2}, Mikio Okazaki³, Kaho Kanno¹, Yuhei Komoda¹, Fumiaki Shikata¹, Mie Kurata^{4

5}, Noritaka Ota¹, Yoshiaki Kubota⁶, Hirotsugu Kurobe¹, Takashi Nishimura¹, Junya Masumoto^{4

5}, Shigeki Higashiyama^{2

7

8}, Hironori Izutani¹

Affiliations

¹ Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, Japan.
² Department of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Japan.
³ Department of General Thoracic Surgery, Okayama University Graduate School of Medicine, Okayama, Japan.
⁴ Department of Pathology, Division of Analytical Pathology, Ehime University Graduate School of Medicine, Toon, Japan.
⁵ Department of Pathology, Proteo-Science Center, Toon, Japan.
⁶ Department of Anatomy, Keio University School of Medicine, Tokyo, Japan.
⁷ Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan.
⁸ Department of Molecular and Cellular Biology, Research Center, Osaka International Cancer Institute, Osaka, Japan.

Abstract

Objectives: The molecular mechanisms underlying post-operative pericardial adhesions remain poorly understood. We aimed to unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis.

Methods and results: We visualized cell-based tissue dynamics during pericardial adhesion using histological evaluations. To determine the molecular mechanism, RNA-seq was performed. Chemical inhibitors were administered to confirm the molecular mechanism underlying adhesion formation. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analyses showed that arterioles excessively sprouted from pericardial tissues after the accumulation of neutrophils on the heart surface in mice as well as 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 tissue but not in quiescent vessels in the heart. SMAD2/3 and ERK activation was observed in sprouting vessels. The simultaneous abrogation of PI3K/ERK or TGF-β/MMP9 signaling significantly decreased angiogenic sprouting, followed by inhibition of adhesion formation. Depleting MMP9-positive neutrophils shortened mice survival and decreased angiogenic sprouting and fibrosis in the adhesion. Our data suggest that TGF-β/matrix metalloproteinase-dependent tissue remodeling and PI3K/ERK signaling activation might contribute to unique angiogenesis with dedifferentiation of vascular smooth muscle cells from the contractile to the synthetic phenotype for 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.

Keywords: angiogenesis; arteriole; fibrosis; mouse model; pericardial adhesions.