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Experimental autoimmune encephalomyelitis potentiates mouse mast cell protease 4-dependent pressor responses to centrally or systemically administered big endothelin-1

Desbiens, L;Lapointe, C;Gendron, L;Gharagozloo, M;Vincent, L;Pejler, G;Gris, D;D'Orleans-Juste, P;

Multiple sclerosis is a neurodegenerative disease affecting predominantly female patients between 20 and 45 years of age. We previously reported the significant contribution of mouse chymase mMCP-4 in the synthesis of endothelin-1 in healthy mice and in a murine model of experimental autoimmune encephalomyelitis (EAE). In the current study, cardiovascular effects of ET-1 and big-ET-1 administered systemically or intrathecally (i.t.) were assessed in the early preclinical phase of EAE in telemetry instrumented/conscious mice. Chymase-specific enzymatic activity was also measured in the lung, brain and mast cells extracts in vitro. Finally, the impact of EAE immunization was studied on the pulmonary and the brain mRNA expression of different genes of the endothelin pathway, IL-33, and mature TNF-. Systemic or i.t. administered big-ET-1 triggered increases in blood pressure in conscious mice. One week post-EAE, the pressor responses to big-ET-1 were potentiated in WT but not in mMCP-4 KO mice. EAE triggered mMCP-4 specific activity in cerebral homogenates and peritoneal mast cells. Enhanced pulmonary, but not cerebral prepro ET 1 and IL-33 mRNA were found in KO mice and further increased one week post EAE-immunization, but not in wild type animals. Finally, TNF- levels were also increased in serum from mMCP-4 KO mice, but not wild type, one week post-EAE. Our study suggests that mMCP-4 activity is enhanced both centrally and systemically in a mouse model of EAE. SIGNIFICANCE STATEMENT: N/A. The American Society for Pharmacology and Experimental Therapeutics.