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Unique angiogenesis from cardiac arterioles during pericardial adhesion formation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE182735 | GEO | 2022/01/10

REPOSITORIES: GEO

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Project description:Collagen deposition is a key process during idiopathic pulmonary fibrosis (IPF); however, little is known about the dynamics of collagen formation during disease development. Tissue samples of early stages of human disease are not readily available and it is difficult to identify changes in collagen content, since standard collagen analysis does not distinguish between 'old' and 'new' collagen. Therefore, the current study aimed to (i) investigate the dynamics of new collagen formation in mice using bleomycin-induced lung fibrosis in which newly synthesized collagen was labelled with deuterated water and (ii) use this information to identify genes and processes correlated to new collagen formation from gene expression analysis. Lung fibrosis was induced in female C57BL/6 mice by bleomycin instillation and sacrificed. Animals were sacrificed at 1 to 5 weeks after fibrosis induction. Collagen synthesized during the week before sacrifice was labelled with deuterium by providing mice with deuterated drinking water. After sacrifice, lung tissue was collected for microarray analysis, determination of new collagen formation, and histology. Deuterated water labelling showed a strong increase in new collagen formation already during the first week after fibrosis induction and a complete return to baseline at five weeks. Correlation of new collagen formation data with gene expression data revealed fibrosis specific processes, of which proliferation was an unexpected one. This was confirmed by measuring cell proliferation and collagen synthesis simultaneously using deuterated water incorporation. Furthermore, new collagen formation strongly correlated with gene expression of e.g. elastin, tenascin C, MMP-14, lysyl oxidase, and type V collagen. These data demonstrate, using a novel combination of technologies, that proliferation and extracellular matrix production are correlated to the core process of fibrosis, i.e. the formation of new collagen. In addition, it identified genes directly correlated to fibrosis, thus providing more insight into the aetiology of IPF. Total RNA was obtained from mouse lungs at timepoint 0 as a control (n = 7) or timepoints 1 (n = 7), 2 (n = 6), 3 (n = 6), 4 (n = 6) or 5 (n = 6) weeks after bleomycin-instillation to induce lung fibrosis.

Project description:Rationale: Adhesion formation is a frequent complication after abdominal surgery. Adhesion formation might be reduced by laparoscopic surgery, however sound evidence is lacking. Colorectal surgery would be a good clinical model to investigate adhesion formation between open and laparoscopic surgery because of the adhesion formation propensity of colorectal surgery. However, a randomized controlled study to provide direct evidence is unlikely because of large numbers of patients needed for such a trial and the difficulty to check for adhesion formation at second surgery. Therefore we investigate adhesion formation after laparoscopic and open colorectal surgery for malignancy at liver surgery for metastases. Objective: The aim of our study is to compare the incidence of adhesions after laparoscopic versus open surgery for colorectal malignancies during liver resection for colorectal metastases. Study design: The study is designed as a prospective observational cohort study. Study population: All consecutive, adult patients undergoing laparotomy or laparoscopy for intended liver resection or radio frequency ablation for liver metastases of a colorectal malignancy in whom inspection of the middle and lower abdomen is possible to map adhesions. Main study parameters/endpoints: * Primary endpoint is incidence of adhesions to the ventral abdominal wall around the site of the original incision. * Secondary endpoints are episodes of bowel obstruction between index surgery and liver surgery; total incidence of adhesions; extent of adhesions; Zühlke classification of adhesions; performance of adhesiolysis; duration of adhesiolysis; peroperative complications: enterotomy, seromuscular injury, inadvertent organ injury during adhesiolysis; postoperative complications: delayed diagnosed perforation, SAE’s. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This study is an observational study. The existence of adhesions will be assessed during laparotomy or laparoscopy for the treatment of liver metastases. The laparotomy is indicated for medical treatment and should not be enlarged solely for the assessment of adhesions nor will the operating time be influenced for this purpose. Adhesions and peroperative complications have to be scored by the operating surgeon during or directly after surgery. The postoperative complications have to be scored during the postoperative course by the doctors on the ward. These assessments do not interfere with the treatment of the patients.

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Unique angiogenesis from cardiac arterioles during pericardial adhesion formation

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