Endothelium-dependent remote signaling in ischemia and reperfusion: Alterations in the cardiometabolic continuum

Intact endothelial function plays a fundamental role for the maintenance of cardiovascular (CV) health. The endothelium is also involved in remote signaling pathway-mediated protection against ischemia/reperfusion (I/ R) injury. However, the transfer of these protective signals into clinical practice has been hampered by the complex metabolic alterations frequently observed in the cardiometabolic continuum, which affect redox balance and inflammatory pathways. Despite recent advances in determining the distinct roles of hyperglycemia, insulin resistance (InR), hyperinsulinemia, and ultimately diabetes mellitus (DM), which define the cardiometabolic continuum, our understanding of how these conditions modulate endothelial signaling remains challenging. It is widely accepted that endothelial cells (ECs) undergo functional changes within the cardiometabolic continuum. Beyond vascular tone and platelet-endothelium interaction, endothelial dysfunction may have profound negative effects on outcome during I/R. In this review, we summarize the current knowledge of the influence of hyperglycemia, InR, hyperinsulinemia, and DM on endothelial function and redox balance, their influence on remote protective signaling pathways, and their impact on potential therapeutic strategies to optimize protective heterocellular signaling.

Automated summary

Intact endothelial function is crucial for cardiovascular health, but metabolic alterations in the cardiometabolic continuum hinder the transfer of protective signals in clinical practice. Hyperglycemia, insulin resistance, hyperinsulinemia, and diabetes mellitus affect endothelial signaling and may impact therapeutic strategies. Further research is needed to fully understand the complex interplay between these conditions and endothelial function.