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.
Highlights
Hemostasis and angiogenesis are two closely interlinked physiological processes that upon vascular injury harmoniously operate to re-establish the microcirculation to its former state [1]
We examined whether an increase in clot size, and the resulting prolongation of pericellular hypoxia, correlated with increased blood cell (BC) pro-angiogenic factor expression, by measuring Vascular Endothelial Growth Factor (VEGF) levels in clot supernatants obtained from 7 day coagulated blood cultures with a blood incubation volume (BIV) of 1, 1.5 and 3ml
While the molecular players involved in the induction of post-wound angiogenesis are relatively well characterized [1,4,5], only little is yet known about the mechanism(s) that regulate where and, more enigmatically, when this occurs
Summary
Hemostasis and angiogenesis are two closely interlinked physiological processes that upon vascular injury harmoniously operate to re-establish the microcirculation to its former state [1]. It is not surprising that the two processes are tightly controlled, to ensure that angiogenesis is only triggered once hemostasis has been safely completed. This is evident during wound healing, where angiogenesis does not begin before three days after wounding [1,3]. While it is generally accepted that these factors, and their induced cellular responses, are important components of a greater regulatory mechanism [4,5], an overarching theory which could explain how hemostasis and angiogenesis are coordinated, in a spatiotemporal manner, is still lacking
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