Venous endothelial injury in neuroinflammatory disease. Alterations in normal flow induced by changes in outflow resistance or valve failure lead to endothelial disturbances that provoke localized inflammatory responses, which may intensify immune activation, leading to demyelination and disability in MS. Flow sensors that may be dysregulated include MKP-1, KLF2, and KLF4, which control adhesion molecule, eNOS, and blood-brain barrier function and iron deposition. Venous valve structural and regulatory components that might be dysregulated in this schema include α9-integrin/fibronectin (FNIIIa), Ephrin B2/EphB4, FOXC2/Prox1/NFATC1, and VEGFR-3. Abbreviations: eNOS, endothelial nitric oxide synthase; FOXC2, Forkhead box protein C2; KLF, Krueppel-like factor; MKP, mitogen-activated protein kinase phosphatase; MS, multiple sclerosis; NFATC1, nuclear factor of activated T-cells, cytoplasmic 1; VEGFR, vascular endothelial growth factor receptor.
Alexander et al. BMC Medicine 2013 11:219 doi:10.1186/1741-7015-11-219