Sustained changes in blood flow elicit adaptive changes in blood vessel size, wall thickness, or both (vascular remodeling) through a signaling pathway that involves the generation of reactive oxygen species (ROS), including superoxide. ROS have also been implicated in vascular inflammation and the recruitment and activation of leukocytes at the arterial wall (processes central to development of atherosclerotic changes), leading Tang et al. to investigate the role of inflammation in blood flow–dependent vascular remodeling. Unlike wild-type mice, mice lacking myeloid differentiation protein-88 (MyD88, an adaptor protein involved in signaling pathways leading to production of inflammatory cytokines) failed to respond to a sustained decrease in blood flow through the common carotid artery with a decrease in vessel diameter (inward remodeling). Indeed, they showed maladaptive arterial wall thickening. Decreased blood flow led to a MyD88-dependent increase in superoxide production, as well as the production of various cytokines and chemokines and the transient recruitment of leukocytes (predominantly macrophages). Cytokine production was MyD88-dependent; moreover, a combination of pharmacological and genetic approaches indicated that both production of inflammatory cytokines, such as IL-1β, and inward remodeling depended on superoxide. Flow-mediated inward remodeling was also blocked by macrophage depletion; however, whereas macrophage activation required MyD88, their initial recruitment did not. Bone marrow reconstitution experiments indicated that cytokine production depended on MyD88 in intrinsic vascular cells, whereas inward remodeling required its presence in bone marrow–derived cells as well. The authors thus conclude that inflammation is critical to flow-mediated inward vascular remodeling, with MyD88-mediated signaling playing distinct roles in both intrinsic vascular cells and infiltrating leukocytes.
P. C. Y. Tang, L. Qin, J. Zielonka, J. Zhou, C. Matte-Martone, S. Bergaya, N. van Rooijen, W. D. Shlomchik, W. Min, W. C. Sessa, J. S. Pober, G. Tellides, MyD88-dependent, superoxide-initiated inflammation is necessary for flow-mediated inward remodeling of conduit arteries. J. Exp. Med. 205, 3159–3171 (2008). [Abstract] [Full Text]