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Sure like to get my mitts on this one, anyone have anything or is this a repeat, seems to be from yesterday. Plus would appreciate tips on how to shorten the url's lol.

Copyright © 2009 Published by Elsevier Ireland Ltd.

Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter

"Angiogenesis" is mentioned + stiffened blood vessel linings. Wonder if that would extend to other veins like in the neck for instance, and at some point, that accounts for loss of flexibility, and inability (all structural considerations aside like bone pushing into it for example) of the vessel to "bounce back", and at that point, the stenosis stays that way, with minimal amount of re-inflation to it's ordinary diameter, almost like the difference between a flexible hose that collapses, but inflates when water goes through it, and a solid copper pipe with a dent in it that doesn't readily assume it's normal shape without angioplasty.


What the heck I'll just put the abstract in here:

Abstract
Multiple sclerosis (MS) is primarily considered an inflammatory demyelinating disease, however the role of vasculature in MS pathogenesis is now receiving much interest. MS lesions often develop along blood vessels and alterations in blood brain barrier structure and function, with associated changes in the basement membrane, are pathological features. Nevertheless, the possibility of angiogenesis occurring in MS has received little attention. In this study we used triple label enzyme immunohistochemistry to investigate blood vessel density and endothelial cell proliferation in MS samples (n = 39) compared with control tissue to explore evidence of angiogenesis in MS. The results showed that in all MS samples examined blood vessel density increased compared with controls. The greatest increase was found in subacute lesions where numbers of positively stained vessels increased from 43.9 ± 8.5% in controls to 84.2 ± 13.3% (P = 0.001). Furthermore, using an antibody against endoglin (CD105), a specific marker of proliferating endothelial cells, which are characteristic of angiogenesis, we have shown that vessels containing proliferating endothelial cells were more pronounced in all MS tissue examined (normal-appearing white matter, acute, subacute and chronic lesions, P ≥ 0.027) compared with control and this was greatest in the MS normal-appearing white matter (68.8 ± 19.8% versus 10.58 ± 6.4%, P = 0.003). These findings suggest that angiogenesis may play a role in lesion progression, failure of repair and scar formation.

Frankly news like this really makes my day.
Dr. Z's research should offshoot into multiple areas. This will ensure:
1) Actual research data is available for everyone (including sceptics)
2) Vascular diseases as underlying issue for lot of diseases will grow into a new discipline of its own
3) It will be difficult for anyone to stop the interest in this area

Great going ...

sbr487 wrote:Frankly news like this really makes my day.
Dr. Z's research should offshoot into multiple areas. This will ensure:
1) Actual research data is available for everyone (including sceptics)
2) Vascular diseases as underlying issue for lot of diseases will grow into a new discipline of its own
3) It will be difficult for anyone to stop the interest in this area

Great going ...

Btw, Zamboni's paper was used as a reference for this too.

Here's a salient fair use quote from the paper:
(EC=Endothelial Cells, angiogenisis is collaterals)

Recently chronic cerebrospinal venous insufficiency due to extracranial
venous stenosis was suggested to be an important feature of MS
[26]. Restricted outflow of blood from the brain might lead to blood
volume back-log and increased transmural pressure. The EC pheno-
type can be altered in response to mechanical forces and significant
continuous haemodynamic abnormalities alter EC function and
therefore downstream signalling [1]. As a result, neuroprotective
mechanisms such as ischaemic preconditioning may be stimulated.
Alternatively either redox imbalance or ‘virtual’ hypoxia which are
believed to play a role in MS [10,22] might induce EC activation
in NAWM, initiate angiogenesis and could explain these changes.

[1] W.C. Aird, Phenotypic heterogeneity of the endothelium: II. Representative vascular beds, Circ. Res. 100 (2007) 174–190
[10] U. Graumann, R. Reynolds, A.J. Steck, N. Schaeren-Wiemers,Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult, Brain Pathol. 13 (2003) 554–573.
[22] B.D. Trapp, P.K. Stys, Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis, Lancet Neurol. 8 (2009) 280–291.
[26] P. Zamboni, R. Galeotti, E. Menegatti, A.M. Malagoni, G. Tacconi, S. Dall’Ara, I. Bartolomei, F. Salvi, Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis, J. Neurol. Neurosurg. Psychiatry 80 (2009) 392–399.
Excited yet? About the "blood volume back log"? ;)

Looks like Dr.Z is going to be a hero in more ways than one.
His work has given new area for young researchers to work on.
Budding researchers planning to research on genetic and immune area for MS will definitely have a second thought.
Of course, due credit should also go to people who brought the topic of blood reflux issue in MS from time to time.
Sometime life can be very harsh on research scientists. Probably that explains why so few people are ready to enter this area and prefer to take the beaten path.

Wow. That is cool.

I found this interesting too - changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. I have been supposing for a while that the fibrin/scars/lesions are a protective mechanism more than a "normal" scarring - a protection from further injury, rather than a reaction to an injury. I am finding it hard to express the nuance right now...

To shorten urls, try http://www.tinyurl.com. For instance, I did a search for the abstract you outlined, and took it to tiny url for this - http://tinyurl.com/mark-abstract.

Clear as mud.

Johnson wrote:Wow. That is cool.

I found this interesting too - changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. I have been supposing for a while that the fibrin/scars/lesions are a protective mechanism more than a "normal" scarring - a protection from further injury, rather than a reaction to an injury. I am finding it hard to express the nuance right now...

To shorten urls, try http://www.tinyurl.com. For instance, I did a search for the abstract you outlined, and took it to tiny url for this - http://tinyurl.com/mark-abstract.

Clear as mud.

Not only that but the number of blood vessels containing "proliferating endothelial cells" were markedly higher in ALL the NAWM (Normal Appearing White Matter) vs. controls. In the normal controls, the number of CD105 containing vessels was around 10%. In the NAWM of MS patients it was 70%. In acute lesions it was 40%. In subacute lesions 60%. Chronic lesions were around 40% too.

Go figure, the marker for endothelial proliferation, and one of the biomarkers for collateral formation, are 4-7x higher in MS patients. Huh. Don't that beat all. You will find the same markers present when collaterals form around tumors for instance. Could it be that a brain in a constant state of hypoxic type injury, lack of oxygen, due to reflux, is circling the wagons and trying to protect itself? I think the body is smarter than all of us combined sometimes.

Is it any wonder that Zamboni wants ALL specialties to come together on this?

But they don't say whether the "MS" causes the CD105 to elevate, or vice versa. Back to chicken>egg.

CD105 is like a messenger, it normally just makes our endothelial linings grow. Except in the case of injury, obstruction, (think tumors, maybe stenosis wink wink), also in hypoxic conditions, then it rushes to the scene of the crime and says "hey grow some more vessels here would ya?". But it also has the feature of growing more lining on the vessel walls too. This is where I think rigidity might come into play and keep a stenotic vessel stuck after a period of time, maybe years. CD105 doesn't necessarily mean you will grow a collateral out of thin air wherever it is present, but it is present wherever collaterals are.

Anyways I know there are many other factors (VEGF, PECAM-1) that come into play here so not trying to oversimplify.

Here's a bit more on CD105 (endoglin):

Endothelial cells lacking endoglin do not grow because TGF-/ALK1 signalling is reduced and TGF-/ALK5 signalling is increased. Surviving cells adapt to this imbalance by downregulating ALK5 expression in order to proliferate. The ability of endoglin to promote ALK1 signalling also explains why ectopic endoglin expression in endothelial cells promotes proliferation and blocks TGF--induced growth arrest by indirectly reducing TGF-/ALK5 signalling. Our results indicate a pivotal role for endoglin in the balance of ALK1 and ALK5 signalling to regulate endothelial cell proliferation. http://www.nature.com/emboj/journal/v23 ... 0386a.html

thanks, Mark. Terrific paper, and a convergence of much research on slowed perfusion, hypoxic injury and now angiogenesis. Yup, looks a lot like an oxygen starved brain trying to reroute and make some drainage.
cheer

Hello CureIous,
An easy way to refer to BioMed papers is the Pubmed site and the PMID number. The very interesting paper you found is:

http://www.ncbi.nlm.nih.gov/pubmed/

PMID: 20036712

By looking at the site it will tell you the Jounal the article is/will be published in. If it costs to get the full article, 31 USD in this case, sometime free. You can find the corresponding author if you want to contact them.

Its an amazing resource for abstracts. Much different from days I spent in our School of Pharmacy library, searching through microfiche. Now a search takes seconds. Happy reading - all 19 million of them.

MarkW

CureIous wrote:"Angiogenesis" is mentioned + stiffened blood vessel linings. Wonder if that would extend to other veins like in the neck for instance, and at some point, that accounts for loss of flexibility, and inability (all structural considerations aside like bone pushing into it for example) of the vessel to "bounce back", and at that point, the stenosis stays that way, with minimal amount of re-inflation to it's ordinary diameter, almost like the difference between a flexible hose that collapses, but inflates when water goes through it, and a solid copper pipe with a dent in it that doesn't readily assume it's normal shape without angioplasty.

"Stiffened blood vessel linings" got me thinking about some of the epidemiological studies that show that there is a higher MS incidence in northern climates and an even higher incidence in land-locked areas. Vitamin D was looked at as being a factor and some have wondered whether diet plays a role (i.e. eating less fish etc.). Could it also be, simply, that these high incidence areas are also colder and have low humidity (stiffening the blood vessel linings further)?

Say one is genetically predisposed to develop CCSVI and is also exposed to lower vitamin D levels, smoking, a diet rich in red meat, and a colder climate with low humidity?

Perhaps such conditions would create a perfect MS/CCSVI storm and explain these geographical quirks as well as fitting in with the CCSVI model?

Thoughts?