Abstract
ObjectivesThe 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 ResultsWe 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.ConclusionsOur findings provide new insights in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues.
Highlights
Pericardial adhesions are frequently recognized in repeat open-heart surgeries and complicate the procedure [1, 2]
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
The ratios of epicardial erosion defined as discontinuous epicardium significantly increased (p < 0.001) at the third hour after injection (Figure 1F), while intact epicardia stained by immunohistochemical staining with GPM6A, which is known as a marker of mesothelial cells [22], was observed in the preinjected or blood-injected mice using a previously established bleeding model [19] (Supplementary Figure 1)
Summary
Pericardial adhesions are frequently recognized in repeat open-heart surgeries and complicate the procedure [1, 2]. The heart consists of various cell types, including cardiac myocytes, myofibroblasts, vascular smooth muscle cells (VSMCs), vascular endothelial cells, and mesothelial cells [3]. Of the various cell types in the pericardial cavity, mesothelial cells play a central role as the initiators of adhesion formation through multi-step reactions after pericardiotomy [5]. Previous investigations using a bacterial toxin-induced pericardial adhesion model in sheep demonstrated that mesothelial cell transition from adhesion to free-floating type in the pericardial cavity induces inflammatory reactions [6,7,8]. New blood vessels have been observed in collagendeposited areas, the temporal cell behaviors of endothelial cells, myofibroblasts, and their source tissues during adhesion formation are poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
