Background and Purpose: Fibroblast Growth Factor (FGF), VEGFR2, and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35-55-induced EAE prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi-kinase inhibition of FGFR1-3, CSF1R and VEGFR2 by AZD4547 may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model. Experimental Approach: Female C57BL/6J mice were treated with AZD4547 (6.25 mg kg-1 or 12.5 mg kg-1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (day 18/20 p.i.) and the chronic phase of EAE (day 41/42 p.i.). Key Results: In the prevention experiment, treatment with AZD4547 prevented severe first clinical episodes by 66.7 or 84.6% respectively. Mice treated with 12.5 mg kg-1 of AZD4547 hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, treatment with AZD4547 resulted in a long-lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased in both experimental approaches. Conclusion and Implications: Multi-kinase inhibition by AZD4547 in a well-tolerated dose of 1 mg kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.

Background and purpose: The thromboxane A2 receptor (TP) plays an eminent role in the pathophysiology of endothelial dysfunction and cardiovascular disease. Moreover, its expression is reported to increase in the intimal layer of blood vessels of cardiovascular high-risk individuals. Yet it is unknown, whether TP upregulation per se has the potential to affect the homeostasis of the vascular endothelium. Experimental approach and key results: Here we report that increasing endothelial expression of both human TP isoforms induces endothelial cell tension and aberrant cell morphology, affects focal adhesion dynamics and inhibits the angiogenic capacity of human endothelial cells in vitro and in vivo, whereas TP knockdown exerts opposing effects. Combined global transcriptome, lipidomic, functional live-cell and validating expression analyses reveal that endothelial TP upregulation induces cyclooxygenase-2 in a Gi/o and Gq/11-dependent manner, thereby promoting its own activation via the auto/paracrine release of TP agonists, such as prostaglandin H2 or prostaglandin F2 but not thromboxane A2. Consequently, this TP-dependent angiostatic feedback loop is disrupted by pharmacological TP or cyclooxygenase-2 inhibition and by genetic reconstitution of prostaglandin H2-metabolizing prostacyclin synthase even in the absence of functional prostacyclin receptor expression. Further mechanistic analyses of downstream TP effectors disclose that the TP induces endothelial cell tension, focal adhesion dysregulation and angiostatic effects via a ROCK-LIMK2-myosin II-dependent signal transduction pathway and downregulates important mediators of endothelial cell homeostasis, e.g. VEGFR-2. Conclusions and implications: Our work uncovers a previously unrecognized mechanism, by which pathological endothelial upregulation of the TP could directly foster endothelial dysfunction, vascular rarefaction and systemic hypertension.