Redox Regulation of Microvascular Physiology and Pathophysiology: Insights into Therapeutic Strategies and Limitations

Significance: Oxidative mechanisms contribute to both vascular function and pathogenesis of many diseases, but their role in the microvasculature remains poorly understood. Recent Advances: The role of reactive oxygen and reactive nitrogen species (ROS/RNS) in the vasculature has been well-established for years. Our knowledge of microvascular responses to ROS/RNS has relied on extrapolation of studies performed in large vessels or cultured endothelial cells from large vessels. In healthy tissue, ROS/RNS are implicated in microvascular cell survival and death, angiogenesis, vasodilation, and barrier function, and, in disease, they contribute to increased permeability, leukocyte extravasation, and inflammation. Redox-mediated microvascular dysfunction underlies a multitude of conditions, including cardiovascular diseases, autoimmune diseases, infectious diseases, hemoglobinopathies, inflammatory diseases, vasculitides, and metabolic diseases. Critical Issues: New single-cell RNA sequencing studies reveal that endothelial cells from different vascular beds have unique gene signatures. Moreover, microvessels respond differently than large vessels, yet findings are frequently extrapolated across vascular beds. Technical challenges have limited our ability to reliably link alterations in ROS/RNS levels to microvascular outcomes. Moreover, successful therapeutics targeting redox signaling in general and in the microvasculature in particular are lacking. While numerous associations exist between common diseases and the microvasculature, the precise contribution of redox-mediated microvascular dysfunction to disease pathogenesis has been challenging. Future Directions: Additional research in organ-specific microvasculature focusing on the redox mechanisms underlying microvascular function and dysfunction is needed, as well as the development of new targeted therapeutics that can be locally delivered. Comparison of redox responses between different diseases may uncover general mechanisms to exploit therapeutically. Antioxid. Redox Signal. 43, 566-621.