Rho and Reactive Oxygen Species at Crossroads of Endothelial Permeability and Inflammation

Increased endothelial permeability and inflammation are two major hallmarks of the life-threatening conditions such as acute respiratory distress syndrome and sepsis. There is a growing consensus in the field that the Rho family of small guanosine triphosphates are critical regulators of endothelial function at both physiological and pathological states. A basal level of reactive oxygen species (ROS) is essential for maintaining metabolic homeostasis, vascular tone, and angiogenesis; however, excessive ROS generation impairs endothelial function and promotes lung inflammation. In this review, we will focus on the role of Rho in control of endothelial function and also briefly discuss a nexus between ROS generation and Rho activation during endothelial dysfunction. Extensive studies in the past decades have established that a wide range of barrier-disruptive and proinflammatory agonists activate the Rho pathway that, ultimately, leads to endothelial dysfunction via disruption of endothelial barrier and further escalation of inflammation. An increasing body of evidence suggests that a bidirectional interplay exists between the Rho pathway and ROS generation during endothelial dysfunction. Rac, a member of the Rho family, is directly involved in ROS production and ROS, in turn, activate RhoA, Rac, and Cdc42. A precise mechanism of interaction between ROS generation and Rho activation and its impact on endothelial function needs to be elucidated. By employing advanced molecular techniques, the sequential cascades in the Rho-ROS crosstalk signaling axis need to be explored. The therapeutic potential of the Rho pathway inhibitors in endothelial-dysfunction associated cardiopulmonary disorders needs to be evaluated.