Signalling from dead cells drives inflammation and vessel remodelling.
Death of vascular smooth muscle cells (VSMCs) has been demonstrated in vessel development and in disease, most notably in atherosclerosis, but also after injury and remodelling. VSMC death promotes multiple features of vulnerable plaques, but also induces features of normal vessel ageing and cystic medial necrosis, including loss of VSMCs, elastin fragmentation and loss, increased glycosaminoglycans and speckled calcification. VSMC apoptosis in the absence of efficient phagocytosis also produces inflammation due to secondary necrosis; in contrast, VSMC apoptosis in normal vessels can be silent. We have investigated the consequences of VSMC apoptosis in both disease and during vessel remodelling. We find that VSMCs release specific cytokines dependent upon the mode of cell death; IL-1β predominates during apoptosis, whilst IL-1α predominates during necrosis. Both IL-1α and β promote release of further cytokines from adjacent live cells, in particular IL-6 and MCP-1. The balance of cytokines results in pathology with differing compositions, including inflammation or neointima formation/vascular repair, via direct promotion of VSMC proliferation and migration. Thus, VSMC death can promote either pathology or repair, depending upon the context and cytokine signalling.
Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom. mrb@mole.bio.cam.ac.uk
Martin
M
Bennett
Haixiang
H
Yu
Murray
M
Clarke
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000503:physiopathology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines