Cerebral microvascular endothelium and the pathogenesis of n

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Cerebral microvascular endothelium and the pathogenesis of n

Postby ikulo » Fri Jun 17, 2011 6:38 pm

Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood-brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells.

http://www.ncbi.nlm.nih.gov/pubmed/21676288
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Postby 1eye » Fri Jun 17, 2011 10:37 pm

Does this make any sense?

1. The endothelium** is a single layer of muscle in each person, some 60,000 miles long.

2. The endothelium consists of cells, each one of which has a mitochondrion and a normal DNA nucleus. The job of the mitochondria is to burn oxygen and produce energy. The endothelium layer uses this energy. How? To change the diameter of the vessel. That controls the flow and temperature of the blood throughout the body.

3. The flow will determine to a great extent how much blood and how much cooling and consequently how much sugar and oxygen are delivered to any one point.

4. The temperature influences the rates of all chemical reactions and thus the rates of the burning of the sugar and oxygen reactions.

5. The diameter of the blood vessel controls the blood flow to a very fine degree. A difference of one, when the vessel diameter grows or shrinks between the values 2 and 3, results in a change of diameter by a proportion from 2**4=16 to 3**4=81. This is a fine, fine degree of control. It is under the control of that single layer and all those mitochondria have to be kept fed.

6. If there is a problem in vein endothelium mitochondria, the vein may have trouble delivering cooling, oxygen, or sugar to itself or other cells downstream of it, if it is required to expand, and can’t. The heart gets around this problem by delivering fresh blood to its right side muscles. Veins can’t.

7. If there is a narrowing that keeps deoxygenated blood too long upstream (where it will continue to be used until it is gone) the vein may continue to be unable to expand, because it does not have the oxygen for its own endothelial contraction or expansion. Endothelial cells and their mitochondria downstream of it may inherit this problem by being in the wrong place at the wrong time.

8. After years of this kind of problem, bad things may start to happen to the vein and its brethren downstream. Things don’t look so good upstream, neither.

9. When we are conceived, we start out as 2 cells. Then 4, 8, 16, 32, and so on. As organs and cell types differentiate, the numbers will get less linear, since some cell lines will take longer than others to divide.

It is interesting to speculate that at one time during development, what ended as 60,000 miles of separate veins and arteries, may have been, probably was, fairly short and continuous. Blood didn't have far to go. All veins were once the same vein.


** Changed epi- to endo-. I was half asleep I guess.
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Re: endo vs. epi (...thelium)

Postby NHE » Fri Jun 17, 2011 11:22 pm

1eye wrote:Does this make any sense?

1. The epithelium is a single layer of muscle in each person, some 60,000 miles long.


I think you meant to say endothelium. The prefix epi means outside and refers to cells that line body compartments that are exposed to the outside world, e.g., skin, lung and digestive tract. The prefix endo means inside and refers to cells that line body compartments which are completely inside the body such as blood vessels. In addition, the endothelium is not muscle, but is a specialized cell layer.


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Postby 1eye » Sat Jun 18, 2011 4:03 am

Is it not responsible for vascular expansion and contraction? That is what I understood. If it is, it is, in that sense, a single layer of muscle. That is what I was getting at when I was discussing the need for energy of the endothelium itself. It must have sugar and oxygen too or it too will die. If it is starving, of either, that would be why expansion and contraction of the vessel diameter would be slow, faulty, feeble, or fail. The energy requirement of that one layer of tissue must be one of the largest in the body. Its budget must be a large part of the total calories we use, just changing vessel diameters, because of the sheer square area of the tissue!

Imagine how many kilowatts it would take to, say increase the diameter of all 60,000 miles of endothelium at once by one micron. That's a vessel 9.6 *10^14 (960 trillion) microns long, expanding 1 micron. It would never happen, but you get the idea. A lotta watts.
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Postby Cece » Sat Jun 18, 2011 6:41 am

here is an image:
http://tinyurl.com/6bx9uv7
http://tinyurl.com/6yqj7pa

The innermost layer of the vein is the endothelial cells. Next layer is the smooth muscle cells. Final layer is connective tissue.
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Postby 1eye » Sat Jun 18, 2011 7:24 am

Cece wrote:here is an image:
www.promocell.com/fileadmin/promocell/K ... sels_2.jpg

The innermost layer of the vein is the endothelial cells. Next layer is the smooth muscle cells. Final layer is connective tissue.


All right then. How many of the 60,000 miles of blood vessels have a smooth muscle layer, or the ability to expand and contract? I guess all but the capillaries, which means not all 60,000.

My argument still applies if those vessels have a smooth muscle layer which is actually doing the work of expanding and contracting, or for any other structure which performs that function.

It is *those* cells that are doing the bulk of the work of being alive, and damage to *those* cells can come about through the means that I discussed. The endothelium experiences the problem first, if it lives between the muscle and the source of the sugar and oxygen, the blood, and the problem happens to be that the blood doesn't *have* enough sugar or oxygen in it. If *anything* interferes with this muscle's ability to get sustenance (even a plugged up endothelium, if you can have such a thing), the problem will happen.

OK? Does that make more sense? The question of how the body burns up all that energy, and why do we feel like we have no energy, should be clearer when you look at it that way. It's expanding and contracting all the blood vessels that takes all the work.

For capillaries flow is controlled in a different way. The point to remember, is that the flow control itself requires energy, uses oxygen and sugar, and is vulnerable when the supply is low. If the flow gets stuck in the off position, damage.
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Postby cheerleader » Sat Jun 18, 2011 9:41 am

Thanks for the new paper, ikulo. Hope more researchers continue to look at changes in the endothelium, or endothelial dysfunction, and how that relates to a break in the blood brain barrier in neurovascular disease. I was thrilled to see Dr. Berislav Zlokovic from the University of Rochester discussing his research at the ISNVD conference in Bologna last March.

The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease.


The brain's endothelium is specialized and different from the rest of the body's, because it is responsible for the function of the BBB. We've been seeing more about oxidative stress in MS recently, with the new Lassmann paper...may it continue! Here's the full Lassmann paper:
link

From those who may not have read this ever, or recently, here's the research I put together in 2008 on the endothelium and potential ways to mitigate dysfunction--
http://www.ccsvi.org/index.php/helping- ... ial-health

There are approximately 60,000 miles of blood vessels in an adult human body. This vast network of arteries, veins and capillaries is maintained and a protected by an inner sheath of microscopic cells called “endothelial” cells (from the Greek “endo” meaning within, and “thiele” meaning nipple, which together suggest “deep within our breast”). These many hundreds of thousands of cells, together comprising the “endothelium,” form the inner lining of blood vessels and lymph vessels, forming a thin layer between the vessel walls and the flowing blood, and serving as an interface between the blood and the rest or our body.


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Postby 1eye » Sat Jun 18, 2011 2:50 pm

That's where I got the figure 60,000 miles. I believe it. That's a lotta vessel for a little blood cell to wander around. Any idea what the round trip time is? How comprehensive is the circuit of the blood? Is every drop expected to show up once in a while at every junction?
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Re: vein vs. artery structure

Postby NHE » Sun Jun 19, 2011 2:51 am

Here is a PowerPoint presentation which depicts the differences between vein and artery structure, Blood Vessels and Hemodynamics. The smooth muscle layer in veins is much thinner than it is in arteries. Arteries can contract to help move blood along. However, veins rely upon the contraction of nearby skeletal muscle to help move the blood by compressing the vein. Valves in the vein prevent backwards flow.

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Postby Nola » Sun Jun 19, 2011 5:16 am

if veins rely partly on the action of skeletal muscle, could spasticity and the use of anti-spasticity medications possibly affect this whole system?
</div><div>Every moment of light and dark is a miracle. -- Walt Whitman</div><div>
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Postby 1eye » Sun Jun 19, 2011 11:45 am

In what I said above, I nowhere meant to refer to the muscle layer in blood vessels as needed to move the blood. I realize there are specialized muscles, the heart being the main one, to do that.

I know that the job of the 60,000 mile (give or take) muscle layer is to constrict and to dilate. The evidence for that is in the 4th-power resistance relationship, and the diagram of diameter versus velocity. The reason vein muscle layers are thinner is that pressures are less and the workload is lower.

However they are there, they are super-critical, they take a lot of power to operate, and when the veins are sick, as we mostly know, the whole body can get very very sick. All I am saying is that we should not overlook the flow control function, which draws a lot of power (makes the human body less energy-efficient, if you want to look at it that way - about the same as a gas guzzling muscle car). Even in the capillaries, there are those sphincters controlling flow. Operating them requires oxygen and sugar.
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Postby 1eye » Sun Jun 19, 2011 1:50 pm

To make this concept a bit clearer, if your car is about 20% efficient (and it probably is) that means out of that dollar's worth of gas you bought, you only get to use 20% of it. The rest goes out your tailpipe. And heats up the tar on the road, and wears down your tires, etc. What happened to it? Incomplete combustion, engine friction, road friction, turning, starting and stopping. Part of the energy goes towards moving the gas from the tank to the spark plug, and toward carrying a tankful of it with you. Only $0.20 worth is left over for you.

Same with the human body. Only what we need to be more aware of (maybe in both cases) is the details, so we can see if there is any way to rob Peter to pay Paul. One of these details, I just became aware of is the fourth power relationship between diameter of veins and resistance, and the other is that there are 60,000 miles (give or take) of smooth muscle expanding and contracting blood vessels. That's a detail I can take home to meet my parakeet. I wondered why I got so tired. I wondered why I got so hot. Veins.
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