Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy

Although multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated demyelinating and neurodegenerative disease of the human central nervous system (CNS), its highly complex pathogenesis clearly includes a significant vascular inflammatory component and many therapeutic approaches achieve benefit by direct or indirect effects on cerebrovascular endothelial cells. Cerebral endothelial cells create and separate the compartments of the peripheral circulation and CNS creating the blood-brain barrier (BBB), a selectively permeable boundary layer between these spaces. Interactions between activated leukocytes and cerebral endothelium play essential roles in mediating their trans-BBB diapedesis during normal immune surveillance and during pathogenesis of neuroinflammatory diseases like MS. Extravasation of activated and committed leukocytes from the peripheral circulation through the endothelial layer of the BBB into the CNS milieu is the most fundamental step in formation of MS lesions. During MS pathogenesis, once the activated leukocytes enter the CNS environment, they propagate a massive wave of destruction which culminates in the loss of both myelin/oligodendrocyte complex and neurodegeneration. Multiple clinical and basic scientific observations support endothelial cell 'stress' and apoptosis as a hallmark characteristic of MS. The manipulation of the endothelial biology aiming to block trans-endothelial migration of activated immune cells into the CNS is a potent form of treatment for MS achieving significant reductions in disease activity and new lesion formation. In particular, endothelial microparticles are now well-recognized as important biomarkers and mediators of this type of stress. In this review, we discuss recent findings and new advances in our knowledge regarding leukocyte migration through the endothelial frontier of the BBB and how this can be exploited toward treating MS patients.