Venous endothelial injury in central nervous system diseases

Jonathan S Alexander,Ikuo Tsunoda,Leonard Prouty,Alireza Minagar,Chaitanya Vijay Ganta

doi:10.1186/1741-7015-11-219

Jonathan S Alexander, Ikuo Tsunoda + Show 3 more

Open Access

https://doi.org/10.1186/1741-7015-11-219

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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.

Highlights

The human central nervous system (CNS) can be affected by a number of inflammatory demyelinating diseases
Could neurological disease processes such as Multiple sclerosis (MS) be triggered or intensified in part through venous vascular disturbances? venous disturbances in particular have long been recognized in several forms of neurological disease, we are only recently appreciating how venous structure, programming, and responses contribute to specific features of these diseases
Sakkar et al demonstrated that dexamethasone could induce expression of MAPK phosphatase (MKP)-1 in venous endothelium, effectively recapitulating the protective effect of shear seen in arterial endothelium exposed to laminar shear stress

Summary

Introduction

The human central nervous system (CNS) can be affected by a number of inflammatory demyelinating diseases. In comparison with the arterial environment, lower venous shear stresses combined with increased venous endothelial permeability and responsiveness (to at least some inflammatory mediators) may make venules and veins more susceptible to developing inflammation. Disturbances in flow direction, but not necessarily shear, modulate claudin-5, another component of tight junctions, which shows arteriovenous endothelial heterogeneity, with arterial endothelium expressing higher levels of claudin-5 than venous endothelium [17]. Sakkar et al demonstrated that dexamethasone could induce expression of MKP-1 in venous endothelium, effectively recapitulating the protective effect of shear seen in arterial endothelium exposed to laminar shear stress These events require extracellular regulated kinase (Erk) and Erk 2, cAMP response element binding, and oxidant signaling. KLF2 is an important shear-activated transcription factor which upregulates endothelial nitric oxide synthase (eNOS) and thrombomodulin (TM) expression and reduces plasminogen activator inhibitor-1 (PAI-1) expression [30]

Conclusions

Schaller B

29. Schelling F

83. LeVine SM

Findings

92. Putnam T