Vascular Arginase Is a Relevant Target to Improve Cerebrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Evidence from the Model of Adjuvant-Induced Arthritis

Abstract

Emerging data revealed that rheumatoid arthritis (RA) is associated with higher risk of cerebrovascular diseases. Whereas cerebral endothelial dysfunction is acknowledged as a critical aspect of cerebrovascular diseases, its presence in RA and the mechanisms involved are currently unknown. By using the model of rat adjuvant-induced arthritis (AIA), the present study investigated cerebrovascular reactivity in pressurized middle cerebral arteries (MCA) on day 33 post-immunization. The results revealed that arthritis induced a dramatic decrease in the vasodilatory response to acetylcholine (ACh), ADP, and bradykinin ( n \u2009=\u20097–9 arteries, p \u2009<\u20090.0001). By using nor-NOHA, L-NAME, BH 4 , and Tempol, the results showed that the reduced response to ACh relied on arginase overactivation ( n \u2009=\u20098), low NOS activity ( n \u2009=\u20098), BH 4 deficiency ( n \u2009=\u20099), and excessive superoxide production ( n \u2009=\u20099). Immunohistological analysis revealed an endothelial upregulation of arginase 2 ( p \u2009<\u20090.05, n \u2009=\u20095–6) and NADPH oxidase ( p \u2009<\u20090.05, n \u2009=\u20095–7) while eNOS expression was unchanged in AIA ( n \u2009=\u20096). To assess whether arginase inhibition may be a relevant therapeutic, AIA rats were treated with an arginase inhibitor (nor-NOHA, 40\xa0mg/kg/day, i.p., n \u2009=\u200920 rats) daily from day 10 to day 33 post-immunization. The treatment alleviated the impaired response of MCA to endothelium-dependent agonists, through an increase in NOS signaling and a suppression of BH 4 deficiency and superoxide overproduction. By contrast, it did not change the course of arthritis. In conclusion, arthritis induced a cerebrovascular endothelial dysfunction involving an imbalance in the arginase/NOS pathway. Arginase inhibition appears as a promising therapy beyond anti-rheumatic drugs for reducing the risk of cerebrovascular diseases in RA.