Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis: Effect of anti-rheumatic drugs

• Published in: Atherosclerosis Vol. 274; pp. 77 - 85
• Main Authors: Pedard, Martin, Quirié, Aurore, Totoson, Perle, Verhoeven, Frank, Garnier, Philippe, Tessier, Anne, Demougeot, Céline, Marie, Christine
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.07.2018; Elsevier
• Subjects: Adjuvant-induced arthritis; Animals; Anti-rheumatic drugs; Antirheumatic Agents - pharmacology; Aorta - drug effects; Aorta - metabolism; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Arthritis, Experimental - physiopathology; Brain-Derived Neurotrophic Factor - metabolism; Cardiology and cardiovascular system; Cyclooxygenase Inhibitors - pharmacology; Freund's Adjuvant; Glucocorticoids - pharmacology; Human health and pathology; Immunosuppressive Agents - pharmacology; Life Sciences; Male; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Phosphorylation; Rats, Inbred Lew; Receptor, trkB - metabolism; Signal Transduction - drug effects; Vascular BDNF; Vasodilation - drug effects; Vascular BDNF; Adjuvant-induced arthritis; Anti-rheumatic drugs; nerve growth-factor; nitric-oxide synthase; tnf-alpha; dysfunction; cells; bdnf; improves endothelial function; cardiovascular risk; rheumatoid-arthritis; inflammatory arthritis
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2018.05.004

In rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. The aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. Vascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkBtyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. Our study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis. •AIA results in impaired endothelial BDNF/TrkB pathway.•Vascular BDNF levels are disconnected from the severity of inflammatory symptoms in AIA.•A positive loop exists between vascular BDNF and NO production in AIA.