Endothelial Progenitor Cells: New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk

Abstract

Over the past decade, we have witnessed an exponential growth of interest into the role of endothelial progenitor cells (EPCs) in cardiovascular disease. While the major thinking revolves around EPC angiogenic repair properties, we have used a hypothesis-driven approach to discover disease-related defects in their characteristics and based on these findings, have identified opportunities for functional enhancement, which offer an exciting avenue for translation into clinical intervention. In this review, we focus on two groups; circulating myeloid angiogenic cells (MACs) and late outgrowth endothelial colony forming cells (ECFCs), and will discuss the unique properties and defects of each population, as new insights have been gained into the potential function of each sub-type using current techniques and multiomic technology. We will discuss their role in inflammatory disorders and alterations in mitochondrial function. In addition, we share key insights into the glycocalyx, and propose this network of membrane-bound proteoglycans and glycoproteins, covering the endothelium warrants further investigation in order to clarify its significance in ECFC regulation of vascularization and angiogenesis and ultimately for potential translational therapeutic aspects.

Keywords: cardiovascular; diabetes; endothelial progenitor cells; glycocalyx; inflammation; lupus; mitochondrial function; rheumatoid arthritis.

Figure 1

Schematic diagram highlighting the agents that cause endothelial damage in diseases with a high risk of developing cardiovascular disease (CVD) and potential therapeutic strategies for endothelial repair. The main protagonists of endothelial damage in diseases including rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), diabetes and CVD are reactive oxygen species (ROS), immune complexes, advanced glycation end products (AGEs), oxidized LDL, tumor necrosis factor-α (TNFα), and interferon-α (IFNα). Endothelial damage and activation leads to an increase in adhesion molecules and inflammatory cell infiltration, mitochondrial damage, as well as release of endothelial microvesicles (EMVs), which may instigate recruitment of endothelial progenitor cells (EPCs; myeloid angiogenic cells [MACs] and endothelial colony forming cells [ECFCs]) for endothelial repair. These disease conditions, along with aging, are also thought to change heparan sulfate proteoglycan (HSPG) structure on the cell surface, resulting in altered cell signaling and adhesion of EPCs and defective repair. Various therapeutic strategies could be employed to reduce the initial damage but also novel approaches using mimics of HSPG to target and improve HSPG signaling and repair are under investigation.