Endothelial-Fibroblast Interactions in Angiogenesis and Matrix Remodeling

Revascularization is critical for successful regeneration of ischemic cardiac tissue after injury. To achieve revascularization in engineered cardiac grafts, it is necessary to understand the interactions between major cardiac cell types. The importance of cardiomyocyte-endothelial interactions in angiogenesis is well documented [1]; however, less is known about interactions between endothelial and stromal cells, fibroblasts in particular. Studies indicate that during capillary assembly, fibroblasts (FBs) provide chemical signaling via growth factor expression and endothelial activation and proliferation [2]. In addition, fibroblasts deposit extracellular matrix (ECM) proteins [3] and also play a role in matrix remodeling. The objective of our study was to further investigate the role of endothelial-fibroblast interactions in angiogenesis with a focus on FB regulation of the extracellular mechanical environment. We and others have recently shown that self-assembling peptide nanoscaffold is a promising material for cardiac tissue regeneration, enhancing angiogenesis in vitro and promoting tissue neovascularization in vivo [1, 4–5]. An important advantage of this nanoscaffold is the ability to control its material properties, such as stiffness and rate of MMP degradation, through its sequence and/or concentration [6]. In this study, RAD16-II peptide nanoscaffold was used as a controlled system to test the hypothesis that fibroblasts regulate angiogenesis via modifying the extracellular mechanical environment through mechanisms including cell-mediated scaffold disruption and matrix remodeling.