Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis.
OBJECTIVE
Ischaemic 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
We developed a method to obtain primary human temporal artery derived myointimal cells (HTAMCs) based on the culture of temporal artery sections on Matrigel.


RESULTS
Among the factors tested (platelet-derived growth factor (PDGF)-AB, fibroblast growth factor (FGF)-2, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF)beta, chemokine (C-C motif) ligand (CCL)2, interleukin (IL)6 and IL1beta), PDGF exhibited the strongest activity in inducing HTAMC proliferation and migration. As assessed by protein array, immunoassay and quantitative real-time reverse transcriptase (RT)-PCR, PDGF stimulated matrix proteins (collagen I, collagen III and fibronectin) as well as CCL2 and angiogenin production by HTAMCs. Imatinib mesylate inhibited PDGF-mediated activation of signalling pathways (Src, extracellular signal-regulated kinase (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.


CONCLUSIONS
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 ischaemic complications in large vessel vasculitis.
Lozano
E
E
Vasculitis Research Unit, Department of Internal Medicine, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Segarra
M
M
García-Martínez
A
A
Hernández-Rodríguez
J
J
Cid
M C
MC
D001549:Benzamides; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005109:Extracellular Matrix / Q000187:drug effects; D013700:Giant Cell Arteritis / Q000473:pathology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007797:Laminin; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011509:Proteoglycans; D011743:Pyrimidines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013699:Temporal Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D001549:Benzamides; D004338:Drug Combinations; D006133:Growth Substances; D007797:Laminin; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D011743:Pyrimidines; D011994:Recombinant Proteins; C095477:platelet-derived growth factor AB; C059485:matrigel; D000068877:Imatinib Mesylate; D003094:Collagen