Venous endothelial injury in central nervous system diseases

0 Department of Microbiology and Immunology, LSU Health Sciences Center , 1501 Kings Highway, Shreveport, LA 71130-3932 , USA 1 Department of Pathology, LSU Health Sciences Center , 1501 Kings Highway, Shreveport, LA 71130-3932 , USA 2 Department of Molecular and Cellular Physiology, LSU Health Sciences Center , 1501 Kings Highway, Shreveport, LA 71130-3932 , USA 3 Department of Neurology, LSU Health Sciences Center , 1501 Kings Highway, Shreveport, LA 71130-3932 , USA Venous Alexander et al. endothelial injury in Venous endothelial injury in central nervous system diseases Jonathan S Alexander1*, Leonard Prouty2, Ikuo Tsunoda3, Chaitanya Vijay Ganta1 and Alireza Minagar4 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. Open Access Introduction The human central nervous system (CNS) can be affected by a number of inflammatory demyelinating diseases. This covers a wide range of clinically and neuropathologically heterogeneous conditions, which share some clinical characteristics, but possess distinguishing immunopathological features. Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are two of the most prominent of these inflammatory diseases. Although these conditions have different root causes, mechanisms, and courses, their underlying neuropathologies both exhibit perivenular demyelination. This strikingly significant important finding points to significant contributions by veins in these conditions, and suggests that venous dysfunction or vein-targeted disease processes, (rather than arterial pathology or injury) contributes * Correspondence: 1Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA Full list of author information is available at the end of the article to the development of these inflammatory CNS diseases. Unlike the cerebral arterial system, the spatial organization of cerebral venous networks is more complex and more often asymmetric, with greater structural heterogeneity than cerebral arterial anatomy. Consequently, this half of the circulatory system has been far less studied and understood [1]. Several reviews [2] have evaluated clinical and structural factors in venous contributions to neurologic diseases. In addition to the inflammatory-based view of the pathogenesis of these demyelinating diseases, the past few years has witnessed the emergence of a controversial view about MS. Could neurological disease processes such as MS be triggered or intensified in part through venous vascular disturbances? Although 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. The concept that neurologic disease can be influenced by structural or functional abnormalities of the CNS venous system has raised intense worldwide debate among researchers, with many investigators arguing against its existence. Controlled, careful clinical studies are needed to validate when and how vascular alterations can contribute to forms of CNS injury and inflammation. Here, we provide a discussion on the potential pathogenesis of these diseases, with emphasis on venous endothelial dysfunction in MS, ADEM, and other forms of neuroinflammation. Pathophysiology of MS with emphasis on venous dysfunction MS is a group of immune-mediated demyelinating syndromes associated with neurodegeneration in the human CNS, which causes significant neurological disability in largely younger adults (Noseworthy [3], Compston and Coles [4]). MS can affect both gray and white matter in any region of the CNS. Four distinct clinical patterns of MS are recognized: relapsing-remitting (RRMS), primary progressive MS (PPMS), secondary progressive MS, and progressive relapsing MS. To date, vascular studies in MS have investigated cerebrovascular capillary and large vessel venous endothelial cells that are not always derived from (or strictly relevant to) the CNS [5-7]. There has been less research into the arterial and venous differences in MS. Despite these limitations, vascular contributions in MS do appear to support the notion of the vasculature being an initiating target in MS etiology and not simply a bystander presentation of other disease processes. Perhaps the strongest support for this is the number of MS therapies that have been developed, which target leukocyte binding to activated endothelial cells, a central component of the blood-brain barrier (BBB). Vascular abnormalities in MS also include evidence of increased circulating markers of vascular inflammation, [8-10], which can lead to inflammatory challenges that initiate or exacerbate CNS injury. Magnetic resonance imaging (MRI) studies in MS also indicate longer mean blood-flow transit times, which indicates relatively lower cerebral blood flow in MS plaques, as well as decreased cerebral blood flow and prolonged mean transit time in normal-appearing white matter (NAWM). Decreases in brain blood flow increase with age in MS, with severity and form of MS (PPMS > RRMS) both of which may intensify ischemic injury [2,9,11]. Importantly, in apparently NAWM, the state of ischemia appears to occur before the appearance of plaques [10]. It is unclear whether diminished cerebral flow represents restricted perfusio (...truncated)