ATF-4 and Vascular Injury

Abstract

See related article, pages 378–387 Smooth muscle proliferation and neointimal formation are characteristic features of vascular lesions that develop after vascular injury and contribute to the development of occlusive vascular lesions after percutaneous coronary interventions and in transplant vasculopathy. The traditional model for the development of these vascular lesions has postulated that a complex interplay among locally released growth factors and cytokines, circulating platelets and inflammatory cells, local smooth muscle and endothelial cells, and perhaps circulating precursor cells involving multiple cellular processes such as adhesion, proliferation, migration, and apoptosis is orchestrated at many levels, resulting in vascular stenosis. The temporal and spatial complexity of the overall process and the diverse contributions of various components have provided many opportunities for study, but identifying and linking the various critical steps in the development of occlusive vascular lesions has remained challenging. Although numerous studies examining roles of vascular signaling pathways and vascular transcription factors have been published, a clear picture of how signaling and transcription are intertwined remains elusive. In this issue of Circulation Research , Malabanan et al present a comprehensive series of experiments linking the transcription factor activating transcription factor (ATF)-4 to intimal thickening after injury and identify both upstream and downstream associated growth factor pathways, thereby providing additional insight into the orchestrated activation of transcriptional and signaling pathways in vascular disease.1 The authors initially identified ATF-4 as a potential regulator of neointimal formation through a microarray screen for genes induced in smooth muscle cells (SMCs) by fibroblast growth factor (FGF)-2. FGF-2 has been identified previously as a major smooth muscle mitogen and has been implicated in the pathogenesis of atherosclerosis and restenosis after angioplasty.2–4 FGF-2 is normally stored and rapidly secreted after injury3 and functions in both an autocrine and paracrine fashion. To confirm the microarray …