Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Giant cell arteritis (GCA) is a vascular inflammatory disease involving large and medium sized arteries, particularly the cranial vessels. Inflammation-induced vascular remodeling leads to vascular occlusion and ischemic symptoms and complications including partial or complete visual loss and, in some cases, stroke or other symptoms of vascular insufficiency. Pathogenic mechanisms contributing to this process are incompletely understood although vascular smooth muscle cell (VSMC) acquisition of a myofibroblastic phenotype might be involved. Over-expression of endothelin-1 (ET-1) and its receptors ETAR and ETBR in GCA lesions as well as increased serum concentrations of ET-1 in patients with ischemic complications has been previously reported (Lozano E et al Ann Rheum Dis 2010). The most investigated function of ET-1 in VSMC is vascular tone regulation. In recent years, it has been shown that ET-1 may contribute to myofibroblast differentiation of fibroblasts, a crucial step in lung and skin fibrogenic diseases. Whether ET-1 has similar effects on VSMC contributing to vascular occlusion has not been investigated. The aim of this study is to investigate if ET-1 induces a migratory myofibroblastic phenotype in human temporal artery (TA) -derived VSMC which might contribute to vascular remodeling and ischemic complications.
Methods: Ex vivo culture of TAs into three-dimensional matrix, migration assays using primary cultures of TA-derived VSMC, co-culture of TA-derived VSMC with peripheral blood mononuclear cells. Immunofluorescence and confocal microscopy of TA, qRT-PCR, immunoassay and western-blot.
Results: In GCA lesions ET-1 was mainly produced by inflammatory cells whereas VSMC overexpressed ET-1 receptors which enhanced their ability to respond to ET-1. ET-1 promoted a spread morphology in cultured VSMC and stimulated their migration by inducing focal adhesion kinase (FAK) phosphorylation at Y397 permitting the association with p85 subunit of PI3Kinase which co-localized with FAK at the cell protrusions of migrating cells. Accordingly, inhibition of both FAK and PI3K abrogated ET-1 induced migration. Interestingly, ET-1 treatment of cultured non pathological TAs promoted the disorganization of the artery layers as a consequence of VSMC migration towards the intima layer. Consistently, blockade of ETAR and ETBR with BQ123 and BQ788 antagonists inhibited ET-1 induced VSMC migration and VSMC outgrowth from cultured GCA-arteries as well as reduced Y397FAK phosphorylation in vitro and ex vivo.
Conclusion: ET-1 may be involved in GCA vascular occlusion by promoting VSMC migration towards the intimal layer, a mechanism involving either ETAR or ETBR. Suported by SAF 2014/57708-R, PIE 13/00033 and FEDER.
To cite this abstract in AMA style:Planas-Rigol E, Terrades-Garcia N, Corbera-Bellalta M, Lozano E, Alba MA, Espígol-Frigolé G, Prieto-González S, Segarra M, Hernández-Rodríguez J, Preciado S, Lavilla R, Cid MC. Endothelin 1 Induces a Myofibroblastic Phenotype in Vascular Smooth Muscle Cells. A Mechanism Potentially Contributing to Vascular Remodeling and Intimal Hyperplasia in Giant Cell Arteritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/endothelin-1-induces-a-myofibroblastic-phenotype-in-vascular-smooth-muscle-cells-a-mechanism-potentially-contributing-to-vascular-remodeling-and-intimal-hyperplasia-in-giant-cell-arteritis/. Accessed October 27, 2020.
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