Venous endothelial injury in central nervous system diseases

Abstract

The role of the venous system in the pathogenesis of inflammatory neurological/neurodegenerative diseases remains largely unknown and underinvestigated. Aside from cerebral venous infarcts, thromboembolic events, and cerebrovascular bleeding, several inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and optic neuritis, appear to be associated with venous vascular dysfunction, and the neuropathologic hallmark of these diseases is a perivenous, rather than arterial, lesion. Such findings raise fundamental questions about the nature of these diseases, such as the reasons why their pathognomonic lesions do not develop around the arteries and what exactly are the roles of cerebral venous inflammation in their pathogenesis. Apart from this inflammatory-based view, a new hypothesis with more focus on the hemodynamic features of the cerebral and extracerebral venous system suggests that MS pathophysiology might be associated with the venous system that drains the CNS. Such a hypothesis, if proven correct, opens new therapeutic windows in MS and other neuroinflammatory diseases. Here, we present a comprehensive review of the pathophysiology of MS, ADEM, pseudotumor cerebri, and optic neuritis, with an emphasis on the roles of venous vascular system programming and dysfunction in their pathogenesis. We consider the fundamental differences between arterial and venous endothelium, their dissimilar responses to inflammation, and the potential theoretical contributions of venous insufficiency in the pathogenesis of neurovascular diseases.

Figure 1

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.