title: The Fibrin Matrix Regulates Angiogenic Responses within the Hemostatic Microenvironment through Biochemical Control.
abstract: Conceptually, premature initiation of post-wound angiogenesis could interfere with hemostasis, as it relies on fibrinolysis. The mechanisms facilitating orchestration of these events remain poorly understood, however, likely due to limitations in discerning the individual contribution of cells and extracellular matrix. Here, we designed an in vitro Hemostatic-Components-Model (HCM) to investigate the role of the fibrin matrix as protein factor-carrier, independent of its cell-scaffold function. After characterizing the proteomic profile of HCM-harvested matrix releasates, we demonstrate that the key pro-/anti-angiogenic factors, VEGF and PF4, are differentially bound by the matrix. Changing matrix fibrin mass consequently alters the balance of releasate factor concentrations, with differential effects on basic endothelial cell (EC) behaviors. While increasing mass, and releasate VEGF levels, promoted EC chemotactic migration, it progressively inhibited tube formation, a response that was dependent on PF4. These results indicate that the clot's matrix component initially serves as biochemical anti-angiogenic barrier, suggesting that post-hemostatic angiogenesis follows fibrinolysis-mediated angiogenic disinhibition. Beyond their significance towards understanding the spatiotemporal regulation of wound healing, our findings could inform the study of other pathophysiological processes in which coagulation and angiogenesis are prominent features, such as cardiovascular and malignant disease.
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany; Department of Plastic, Reconstructive, Hand and Burn Surgery, Bogenhausen Hospital, 81925, Munich, Germany.
authors: Ektoras
authors: E
authors: Hadjipanayi
authors: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors: Peer-Hendrik
authors: PH
authors: Kuhn
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Philipp
authors: P
authors: Moog
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Anna-Theresa
authors: AT
authors: Bauer
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Haydar
authors: H
authors: Kuekrek
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Lilit
authors: L
authors: Mirzoyan
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Anja
authors: A
authors: Hummel
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Katharina
authors: K
authors: Kirchhoff
authors: Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital Düsseldorf, 40225, Düsseldorf, Germany; Cambridge University Department of Paediatrics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors: Burak
authors: B
authors: Salgin
authors: Department of Plastic, Reconstructive, Hand and Burn Surgery, Bogenhausen Hospital, 81925, Munich, Germany.
authors: Sarah
authors: S
authors: Isenburg
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany; Department of Plastic, Reconstructive, Hand and Burn Surgery, Bogenhausen Hospital, 81925, Munich, Germany.
authors: Ulf
authors: U
authors: Dornseifer
authors: Department of Plastic, Reconstructive, Hand and Burn Surgery, Bogenhausen Hospital, 81925, Munich, Germany.
authors: Milomir
authors: M
authors: Ninkovic
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany.
authors: Hans-Günther
authors: HG
authors: Machens
authors: Department of Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675, Munich, Germany; Center for Applied New Technologies in Engineering for Regenerative Medicine (Canter), Munich, Germany.
authors: Arndt F
authors: AF
authors: Schilling
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D001777:Blood Coagulation; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix; D005337:Fibrin / Q000378:metabolism*; D006487:Hemostasis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010100:Oxygen; D011485:Protein Binding; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D043925:Angiogenesis Inducing Agents; D005337:Fibrin; D010100:Oxygen