Venous endothelial injury in CNS diseases

[cheerleader]

A new review from the endothelial/neurological departments at LSU (Alexander and Minagar have been looking at vascular connection to MS for almost a decade.)
Full paper online, for free.

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.

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].

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.

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).

It's a good one.
Thanks to Shayk for sending this along to me today---
http://www.biomedcentral.com/1741-7015/11/219

cheer

[Cece]

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).

Oh that is a powerful way to state what the MS therapies are doing and how it relates to the vascular.
Thanks for posting this. I am encouraged by the presence of actual researchers engaging with the ideas. When you say it's from the endothelial/neurological departments, there is neurologist involvement in this? That seems like progress. I'm familiar with Dr. Alexander's work but not Dr. Minagar.

[cheerleader]

Dr. Alireza Minagar is a board certified neurologist who sub-specializes in clinical neuro-immunology and multiple sclerosis. He sees patients with MS and other inflammatory disorders of the brain and spinal cord at the Neurology Clinic of Louisiana State University Health Sciences Center in Shreveport, Louisiana.

Dr. Minagar's research interests involve abnormalities of cerebral endothelial cells in the context of various inflammatory disorders, particularly MS, interactions of cerebral endothelial cells with activated leukocytes, transendothelial migration of leukocytes in MS as well as role of endothelial microparticles in pathogenesis of MS. Dr. Minagar is also involved in a number of clinical research projects related to use of new immuno-modulatory agents for treatment of MS. Dr. Minagar is also interested in the role of various biomarkers in predicting the course of MS and therapeutic response of these patients to immunomodulators.

http://www.lsuhscshreveport.edu/Neurolo ... rosis.aspx


Exactly, Cece! Dr. Minagar looks at endothelial cells, specifically to find ways to modulate leukocyte response....here's a neurologist saying- the blood brain barrier is a vascular element, let's look at blood flow. And let's look at how the venous system differs from the arterial side. About time, huh?
cheer

[Cece]

I just printed off 15 pages of reading for later.
Wow, Dr. Minagar's research interests seem to be spot-on for what we've been talking about for the past four years. Yes, about time, lol. It has to take some bravery for a neurologist to speak up when there has been so much ridiculing.

[1eye]

from http://www.biomedcentral.com/1741-7015/11/219

hemostasis [35]

Hemostasis, as Dr. Tucker points out, happens every time there is a reversal of blood flow from negative to positive or vice versa. This can occur one or more time per heartbeat, with wave interference, and will be stationary, if the wave is standing (meaning any effects of hemostasis will be localized). Perhaps this occurs at lesion sites?

[ttucker3]

I was struck by the line in the paper by Alexander et al (and they reference a paper by Adamson et al, 213) that “…retrograde flow, rather than shear forces, diminishes the venous endothelial solute barrier (note Adamson addresses permeability to water) by decreasing the organization of the endothelial junctional VE-cadherin and occluding … supporting the concept that abnormal flow patterns can dysregulate endothelial barrier properties…” This indicts reverse flow weakens a blood-brain-barrier (BBB) in comparison to one in which the blood flow does not reverse. This seems to be quite consistent with the findings of Cucullo et al (BMC Neuroscience 2011, 12-40) who found that the amount of sheer stress that is associated with venous flow substantially affects blood-brain-barrier tightness. They found that endothelial cells grown ”…under the influence of shear stress formed a significantly more stringent barrier … than parallel cultures grown under static conditions.” (ie under zero flow conditions). They measured a multiple of seven difference in the measured Transendothelial Electrical Resistance Resistance (TEER) between the two cases, with a TEER of 700 vs 100 ohms/sqcm for the flow vs no flow conditions. This TEER ratio between these samples increased from a factor of two after one day to a factor of seven after 30 days, indicating that the time of exposure influences this tightness. (Note, however that neither of these papers refer specially to the permeability of the BBB to leukocyte trans-migration. However the nature of the blood flow clearly has an influence on the properties of the BBB.)
My perception is that a venous obstruction that results in the reflection or reflux of significant venous pulses (more about the nature of such an obstruction below) will cause a standing pressure wave in the vein in which there are nodes of relatively low and non-fluctuating pressure separated by regions of large hypertensive pressure fluctuations. Within the vein and around these non-fluctuating pressure nodes the blood will oscillate back and forth during each cardiac cycle. Such nodes will occur at half wavelength intervals back toward the capillary bed. For typical flow rates and pulse rates these nodes will be separated by perhaps 5 to 7 centimeters. On either side of the nodes (and also on either side of the hypertensive points) the blood flow will change positive to negative and back during each cardiac cycle. Such reversing (counter flow) venous flow points would, from the foregoing therefore, probably cause an altered and weakened blood-brain barrier which could be a very important link in the neuro-vascular disease chain.
A comment now about the nature of obstructions that may give rise to substantial venous reflux pulses. It is probably important to note that most vein stenoses or narrowings are not likely to cause a significant reflux pulse simply because veins under normal conditions are quite compliant (flexible). It means that the passage of a pressure pulse simply causes the normal vein to stretch to allow the passage of that pulse. The vein must be constricted, in some way, from stretching or expanding in diameter. Such constriction may occur with intraluminal (inside the vein) growths like webs, flaps etc, or with thickened areas of vein wall (for example at the valve in the internal jugular vein), or with external forces (for example pressure from a dislocated Atlas vertebrate or from neck muscles). In addition, the obstruction must be fairly abrupt and not distributed to cause pulses reflect. In other words a long gradual obstruction will spread the peak of the reflected pulse over the length of the obstruction and it will not appear as a pulse that would give rise to standing pressure waves.
Trev Tucker

[1eye]

Perhaps also common might be the case where much slower muscular pumping or straining may cause hemostasis or low flow or low velocity to appear and persist long enough or often enough (or both) to damage the BBB, after which those same effects could also take place where they can cause more damage on the brain side of the barrier. I think a reflux does not have to be a jet that reaches far. Maybe Dawson's Fingers are large areas where a persisting reflux caused hemostasis in that pattern. Can we say that specific locations of BBB damage exist in vivo, or are we limited to cadaver studies? If they are localized, maybe we can see a pattern to their formation. Is there a way to image permeability?

[ttucker3]

My perception is that it would be of interest for IRs, when performing the dilation of obstructions, to also note pulse and flow rates and the location of scleroses relative to the obstructions. Finding a correlation between the obstruction/sclerosis distance (through the vein connections) and the half-wavelength of the pulse waveform would be most enlightening.
Trev. Tucker