Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions

Abstract

BackgroundAngiogenesis is a common finding in chronic inflammatory diseases; however, its role in multiple sclerosis (MS) is unclear. Central nervous system lesions from both MS and experimental autoimmune encephalomyelitis (EAE), the animal model of MS, contain T cells, macrophages and activated glia, which can produce pro-angiogenic factors. Previous EAE studies have demonstrated an increase in blood vessels, but differences between the different phases of disease have not been reported. Therefore we examined angiogenic promoting factors in MS and EAE lesions to determine if there were changes in blood vessel density at different stages of EAE.MethodsIn this series of experiments we used a combination of vascular casting, VEGF ELISA and immunohistochemistry to examine angiogenesis in experimental autoimmune encephalomyelitis (EAE). Using immunohistochemistry we also examined chronic active MS lesions for angiogenic factors.ResultsVascular casting and histological examination of the spinal cord and brain of rats with EAE demonstrated that the density of patent blood vessels increased in the lumbar spinal cord during the relapse phase of the disease (p < 0.05). We found an increased expression of VEGF by inflammatory cells and a decrease in the recently described angiogenesis inhibitor meteorin. Examination of chronic active human MS tissues demonstrated glial expression of VEGF and glial and blood vessel expression of the pro-angiogenic receptor VEGFR2. There was a decreased expression of VEGFR1 in the lesions compared to normal white matter.ConclusionsThese findings reveal that angiogenesis is intimately involved in the progression of EAE and may have a role in MS.

Neurological deficits caused by tissue hypoxia in neuroinflammatory disease

“…Vessels initially dilate in response to hypoxia in order to promptly increase local blood supply, and then proliferate to provide the hypoxic region with a richer vascular bed 43 . Similar changes in vessel density occur in MS 44 and have been reported in EAE 45 (see also 46 ).…”

Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor

“…Angiogenesis has Janus-like opposing roles in EAE pathogenesis. Angiogenesis was observed at the margin of demyelination lesions and was involved in the progression of EAE [21,22]. In contrast, it played a protective role in EAE by promoting neuronal remodeling [23].…”

Neuropilin-1 is upregulated in Sjögren’s syndrome and contributes to pathological neovascularization

“…Several potent pro-angiogenic cytokines have been implicated in inXammatory angiogenesis. Of these, vascular endothelial growth factor-A (VEGF-A) and its receptors (VEGFRs) have been demonstrated to play a central role in rheumatoid arthritis (Kurosaka et al 2010), systemic lupus erythematosus (Cioikiewicz et al 2010) and multiple sclerosis (Seabrook et al 2010). In the last few years, other molecules, initially found in neurodevelopment, have been found to be involved in angiogenesis and recently also in the immune system and autoimmunity.…”