![]() During this stage, M1-like macrophages generate inflammatory cytokines and chemokines, as well as bactericidal products such as peroxynitrite anion. It is well-established that in the acute response to tissue injury, immune cells are recruited to combat bacterial infection and to clear necrotic debris. However, before delving into the new insights linking inflammatory signaling, vascular recovery, and tissue repair, it is useful to review the current paradigm. As described below, these elements of tissue repair, i.e., inflammatory signaling and vascular recovery, are inextricably linked. In addition, tissue repair requires restoration of tissue perfusion. It is generally recognized that inflammation and inflammatory signaling plays a critical role during tissue repair. The current paradigm of tissue repair and vascular recovery Understanding the relationship between inflammation, transdifferentiation, and vascular regeneration may lead to a new therapeutic approach to PAD. Periphery artery disease (PAD) involves the dysregulation of vascular repair and inflammation. In the environment of under-perfused tissue, the activated fibroblasts with increased DNA accessibility can now respond to angiogenic cytokines, which provide the transcriptional direction to induce fibroblasts to become endothelial cells. Transdifferentiation of fibroblasts to endothelial cells is initiated by inflammatory signaling which increases DNA accessibility and cellular plasticity. However, we provide new data indicating that fibroblasts may undergo angiogenic transdifferentiation, to directly expand the microvasculature. Heretofore, fibroblasts were not generally believed to be involved in vascular regeneration. Tissue fibroblasts participate in tissue repair by proliferating and generating the extracellular matrix as the structural scaffold for tissue regeneration. Endothelial cells play a major role in angiogenesis, whereas circulating angiogenic cells (primarily of hematopoietic origin) participate in adult vasculogenesis, and monocytes/macrophages have a defining role in the vascular remodeling that is necessary for arteriogenesis. The regeneration of the vasculature is a critical process for tissue repair and involves angiogenesis, adult vasculogenesis, and often arteriogenesis, which processes enable recovery of perfusion to deliver oxygen and nutrients to the repair or rebuild of the tissue. Tissue repair requires the orchestration of multiple processes involving a multiplicity of cellular effectors, signaling pathways, and cell-cell communication. ![]() Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States.
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