Objectives: Ischemic complications occur in 15-20% of patients with giant-cell arteritis (GCA). The aim of our study was to explore the effect of mesenchymal growth factors expressed in GCA lesions on myointimal cell responses related to the development of intimal hyperplasia and vessel occlusion.
Methods and results: We developed a method to obtain primary human temporal artery derived myointimal cells (HTAMC) based on the culture of temporal artery sections on Matrigel. Among the factors tested (PDGF-AB, FGF-2, VEGF, EGF, TGFβ, CCL2, IL-6, IL-1β), PDGF exhibited the strongest activity in inducing HTAMC proliferation and migration. As assessed by protein array, immunoassay and quantitative real-time PCR, PDGF stimulated matrix proteins (collagen-I, collagen-III and fibronectin) as well as CCL2 and angiogenin production by HTAMC. Imatinib-mesylate inhibited PDGF-mediated activation of signaling pathways (Src, ERK and Akt phosphorylation) related to cell motility and survival, efficiently resulting in inhibition of PDGF-induced HTAMC responses. Myointimal cell outgrowth from cultured temporal artery sections from patients with GCA, where multiple interactions take place, was also efficiently reduced by imatinib.
Conclusion: Among several mediators produced in GCA, PDGF has the highest vaso-occlusive potential. PDGF may also contribute to disease perpetuation by stimulating the production of angiogenic factors (angiogenin) and chemoattractants (CCL2). Imatinib-mesylate strongly inhibits PDGF-mediated responses, suggesting a therapeutic potential to limit vascular occlusion and ischemic complications in large-vessel vasculitis.
- Intimal hyperplasia
- Large-vessel vasculitis
- Platelet-derived growth factors
- Vascular smooth muscle cells