Unique angiogenesis from cardiac arterioles during pericardial adhesion formation

The molecular mechanisms underlying postoperative pericardial adhesions are poorly understood. We aimed to unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis. Using a previously established murine model, we successfully visualized the cell-based tissue dynamics during pericardial adhesion and discovered a unique angiogenic process for the induction of fibrosis. Masson's trichrome staining revealed that collagen production was promoted from the fourth day after cardiac injury inflicted by talc injection into the pericardial cavity. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analysis demonstrated 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 cells and myofibroblasts appeared in cytokine-exposed sprouting vessels and adhesion tissues, but not in quiescent vessels in the heart. Additionally, vascular smooth muscle cells were dedifferentiated from the contractile to the synthetic phenotype in heart tissue, and matrix metalloproteinase-dependent tissue remodeling in the pre-angiogenic stage potentially contributed to neovascularization and fibrosis in the pericardial cavity. Our findings will assist in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues. Overall design: To elucidate the molecular mechanism underlying pericardial adhesion, RNA sequencing using Illumina Miseq was performed on samples obtained from heart and adhesion tissues.