THU0312 ADVENTITIAL FIBROBLAST, AN IMPORTANT PLAYER IN GIANT CELL ARTERITIS
Authors: Simon Parreau, Nicolas Vedrenne, Alexis Régent, Laurence Richard, Philippe Sindou, Luc Mouthon, Anne-Laure Fauchais, Marie-Odile Jauberteau, Kim-Heang Ly
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Giant cell arteritis (GCA) is a systemic vasculitis affecting large vessels. The diagnosis is based on the temporal artery biopsy (TAB) which shows a segmental and focal arterial infiltration composed of CD4 T cells and macrophages. It is accompanied by a destruction of the internal elastic layer of the media and a hyperplasia of the intima by proliferation of myofibroblasts (Weyand). The origin of these myofibroblasts is controversial (Ly). Evidences suggest the activation of adventitial fibroblasts into myofibroblasts and their migration into the intima (Stenmark). <h3>Objectives:</h3> The objective of this study was to determine whether adventitial fibroblasts migrate to the intima and thereby contribute to intimal hyperplasia during CGA. <h3>Methods:</h3> Arterial sections from TAB of patients with GCA (n=24) and control subjects (n=24) were analyzed. Immunohistochemical analysis was performed using antibodies directed against fibroblasts (CD90, vimentin), myofibroblasts (alpha smooth muscle actin {ASMA}) and vascular smooth muscle cells (desmin). Staining of prolyl-4-hydroxylase (P4H) and myosin were also performed. Stainings were quantified using the ODPviewer® software (Kamax Innovative System, France) by two double-blind observers. Moreover, co-expression of CD90 with different stainings (ASMA, myosin and P4H) was also performed. Cells in culture were identified by immunocytochemistry using anti-CD90 and markers of activity such as myosin and P4H. Functional assays were performed using culture cells obtained from GCA patients' BATs (n=4) and controls (n=4). The BATs were dissected to separate the adventitia from the other two layers. Each dissected fragment was seeded separately. The proliferation was studied using a bromodeoxyuridine incorporation test under different conditions: DMEM, fetal calf serum (FCS), PDGF and supernatants of cells in culture. The study of migration was performed using a scratch test under the same conditions. <h3>Results:</h3> CD90 was significantly higher in GCA than controls in adventitia and intima. Vimentin and ASMA were significantly higher in the 3 tunics of patients with GCA. Expression of desmin was only present in the media for both groups with no significant difference. P4H was present in adventice significant differences between both groups. The adventitial and intimal CD90+ cells co-expressed P4H, ASMA and myosin more importantly during GCA. Cultured cells from BATs' adventices expressed CD90 and did not express desmin. These cells had a greater myosin staining during GCA and had an increased proliferation ability during GCA in the presence of FCS, PDGF and fibroblast supernatants of control or GCA patients. The migration rates of these cells were also significantly increased during GCA in the presence of FCS or PDGF. <h3>Conclusion:</h3> Vascular remodeling during GCA would start in the adventitial layer with a key role of fibroblasts. Adventitial fibroblasts could be activated into myofibroblasts and acquire proliferative and migratory abilities. They would participate in the intimal hyperplasia, responsible for ischemic complications. Their inhibition could be a therapeutic way to limit these complications. The activating signal of adventitial fibroblasts into myofibroblasts is not yet known during GCA and requires further studies. <h3>References:</h3> [1] Weyand, C.M., Goronzy, J.J., (2014). Clinical practice. Giant-cell arteritis and polymyalgia rheumatica. N Engl J Med. 371, 50-7. [2] Ly, K.H., Liozon, E., Fauchais, A.L., Vidal, E., (2013). Pathophysiology of giant cell arteritis. Rev Med Interne. 34, 392-402. [3] Stenmark, K.R., Yeager, M.E., El Kasmi, K.C., Nozik-Grayck, E., Gerasimovskaya, E.V., Li, M., Riddle, S.R., Frid, M.G., (2013). The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol. 75, 23-47. <h3>Disclosure of Interests:</h3> None declared