Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Abstract

Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood–brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

Acute and chronic demyelinated CNS lesions exhibit opposite elastic properties

“…Notably, transient deposition of soluble fibronectin monomer during acute demyelination phase maybe be functionally different from the formation of insoluble aggregates in chronic demyelination 42 , which have been shown to inhibit OL maturation but promote OPC proliferation 43,44 . The observed patterns of increased fibronectin deposition might also be indicative of the increased angiogenesis common in demyelinated lesions 45 . However, considering that as much as 30–46% of the total area of stiff lesions displayed a significant change in elastic modulus, it is unlikely that the contribution of vasculature alone can explain these differences.…”

Microglial control of astrocytes in response to microbial metabolites

“…In summary, we found that AHR-controlled microglial VEGF-B and TGF-α regulate astrocyte pathogenic activities during EAE. VEGF-A promotes CNS pathology by multiple mechanisms including angiogenesis induction 21 , and microglia 22 and T cell 23 stimulation, but less is known about VEGF-B which does not promote angiogenesis in the CNS 24 and shows neuroprotective effects in some models 25 . Our data suggest that Flt-1 activation in astrocytes by VEGF-B produced by microglia and other sources 26 promotes CNS inflammation, identifying VEGF-B/Flt-1 signaling inhibitors as candidate therapeutics for CNS inflammation.…”

Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes

“…The role of VEGF seems to be pleiotropic. Although VEGF acts as a proinflammatory factor in the early phase of CNS inflammation, its reduced reactivity in the late phase can result in the dysregulation of neural progenitor proliferation, migration, differentiation, and OPC survival and migration to demyelinated lesions [52].…”