Ideas on Endothelial Dysfunction

[Nas]

Hi guys,
So following a discussion last month on this forum about the Blood brain barrier and the testicle blood barrier and how their dysfunction could be the reason why an action that happens in the reproductive system, ejaculation that is, is connected with symptoms in the brain.
Personally I do not know how to theorize about this subject - as I am not really experienced in the medical field, but I have been searching on the possible treatments for Endothelial Dysfunction.
What caught my eyes though was many of the treatments suggested decrease blood pressure even though POIS sufferers experience low blood pressure as a POIS symptoms including me.
Here is the article: https://www.jstage.jst.go.jp/article/ihj/51/1/51_1_1/_article
So I wonder how does that correlate with POIS? ff there is a correlation at all,
and if Endothelial Dysfunction treatment is not suited for POISers since it decreased blood pressure.
Asking the many experts here, since I'm not really suited for this kind of research. lol

[Muon]

I was thinking lately that perhaps the redness in skin prick tests are related to endothelial dysfunction. Skin redness by these test is mainly due to molecules pouring through artery walls and causing reactions (someone should correct me if I'm wrong). What if a vascular endothelial dysfunction causes hyperpermeabilty of the artery walls and stimulates this reaction?

Also if the source of my elevated IL-8 is the endothelial cell then it can create an IL-8 gradient near the endothelium lining attracting neutrophils and/or lymphocytes. Maybe these could migrate through this lining and disrupt it. And what if this happens in the genitourinary system? Does this leads to POIS due to diffusion of semen/sperm/pre-ejaculate?

Anyway I stumbled upon an article just before you posted this thread and could be of interest for treatment purposes:

Angiopoietin‐1 inhibits endothelial permeability, neutrophil adherence and IL‐8 production
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0705259

Here is another one:
Angiopoietin-1 Regulates Brain Endothelial Permeability through PTPN-2 Mediated Tyrosine Dephosphorylation of Occludin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474807/

[FernandoPOIS]

I think it has a relationship. I have varicose veins and low blood pressure.

People with mutations in the MTHFR gene exhibit enzymatic deficiency that leads to homocysteine accumulation and this alters the function of nitric oxide.

I do not know whether the treatment goes through the way of correcting endothelial dysfunction but something might help maybe for the symptoms phase.

I believe that the enzymatic deficiency, genetic characteristic of little connective tissue and problem in the vagus nerve to respond to the mental and physical stresses form a condition that the majority here in the forum suffer.

Again I will mention that I was very impressed with the typical physical characteristics that I saw in the members of the Facebook group. Deficiency of postural musculature, Low muscle mass and large legs compared to torso size It may be that this is a cause of low blood pressure (thinking of the implied physical issue).

Let s discuss about it. This idea may lead us to somewhere.

[Muon]

Hi Fernando,

Yes perhaps plasma leaks through walls and causes low blood pressure. The body could compensate for this effect by raising heart rate (POTS?). I wonder if this can lead to hypovolemia which can also be seen in POTS patients. I have the same low muscle mass.

So Ang-1 could inhibit IL-8 production, that is what the first link I have posted states. So my IL-8 is elevated and could make a case for getting this substance. I don't know if there is a medicine containing Ang-1 or indirect releases it in the body. I'm tired at the moment, if someone could look into this matter and search what receptors are at play here and what medicine can simulate the effect of Ang-1 in the first paper then please post it in this thread, It's late I'm going to bed.

[Nas]

Hi Fernando,

Yes perhaps plasma leaks through walls and causes low blood pressure. The body could compensate for this effect by raising heart rate (POTS?). I wonder if this can lead to hypovolemia which can also be seen in POTS patients. I have the same low muscle mass.

So Ang-1 could inhibit IL-8 production, that is what the first link I have posted states. So my IL-8 is elevated and could make a case for getting this substance. I don't know if there is a medicine containing Ang-1 or indirect releases it in the body. I'm tired at the moment, if someone could look into this matter and search what receptors are at play here and what medicine can simulate the effect of Ang-1 in the first paper then please post it in this thread, It's late I'm going to bed.

It's ok Muon I think I found an article that suggests a treatment method: https://www.sciencedirect.com/topics/medicine-and-dentistry/angiopoietin-1
This article suggests: "Dexamethasone in doses of 8 to 40 mg per day upregulates angiopoietin 1 to stabilize the blood-brain barrier and downregulates VEGF"
What do you think? I'm not explicitly thrilled at trying a chorticosteriod but maybe worth a try?

[nanna1]

Hi All,

  I think histamine is the key that the immune system uses to open the blood vessels and allow large molecules (chemokines) and cells (neutrophils) to pass through. The H1-histamine receptor functions as the keyhole that unlocks/opens the blood vessel. I posted about this here. When histamine binds to the H1 receptor, it activates phospholipase A2 and produces prostaglandins through the arachidonic acid cascade. Ultimately, prostaglandins produced from the arachidonic acid cascade control the blood-brain-barrier.

"One of the most striking actions of prostaglandins of the E and A series is their capacity to dilate peripheral blood vessels and thereby to lower arterial pressure. This vasodilating effect of prostaglandins may be mediated by alterations in circulating blood levels of the hormone(s) or by changes in concentration of prostaglandins in blood vessel walls. Prostaglandins also have been implicated in the regulation of the renin-angiotensin-aldosterone system."
-Prostaglandins: Effects on blood pressure, renal blood flow, sodium and water excretion

"...mechanistic studies of how NO switches on/off the PG/COX pathway have been undertaken and additional pathways through which NO modulates prostaglandin production unraveled."
-Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors.

  The easiest/cheapest way to close the blood-brain-barrier is to take the H1-receptor antiagonist Zyrtec (or Xyzal). Dexamethasone (and all other corticosteroids) function as phospholipase inhibitors (Ref), meaning that they block the release of aracidonic acid. But in general, it seems anything that stops the arachidonic acid cascade will close the BBB and reduce inflammation.

[Nas]

Very interesting Nanna,
I wonder though what would be the cause of H1-histamine activity in the blood ? According to your theory it could be the dormant virus' activity. But what I suggest is that in a case of a dysfunctional Endothelium, the ejaculation process can cause a diffusion of Semen components through the testicles blood barrier which initiates the immune response. Here, there could be two possible cases: 1) The immune system attacks the Semen component increasing the levels of histamine in the blood causing the dysfunction in the Endothelium. 2) We have a general Endothelial dysfunction that makes these Semen components not only get passed the Testicles Blood Barrier but also get passed the BBB.
Although I would like to note that I already tryed different anti-histamines including cetrizine but they didn't do much unfortunately.

[nanna1]

Hi Nas,

You may be on to something. I do think blood vessel health is part of the POIS equation.

Very interesting Nanna,
I wonder though what would be the cause of H1-histamine activity in the blood ? According to your theory it could be the dormant virus' activity. But what I suggest is that in a case of a dysfunctional Endothelium, the ejaculation process can cause a diffusion of Semen components through the testicles blood barrier which initiates the immune response. Here, there could be two possible cases: 1) The immune system attacks the Semen component increasing the levels of histamine in the blood causing the dysfunction in the Endothelium.

(1) is a genetic autoimmune mechanism for POIS. My test results suggest that I do not have genetic autoimmunity (see "Autoimmunity blood test:" section). So for me, (1) would not be the cause of my POIS symptoms. My immune system does not attack healthy cells in my body. However, semen is generally high in prostaglandins (prostate-gland-in, in the prostate gland). Also, you might find this article interesting (Seminal plasma components stimulate interleukin-8 and interleukin-10 release).

2) We have a general Endothelial dysfunction that makes these Semen components not only get passed the Testicles Blood Barrier but also get passed the BBB.

In my test results, I posted the doctors notes from my MRI angiogram (MRA). The doctor found what he believed to be a small bulge (aneurysm) in a blood vessel in my brain on the left side (see "Brain scan:" section). In the doctor's notes, he says "There is no evidence for vessel irregularity, stenosis or other aneurysm formation." In other words, the angiogram did not find anything generally wrong with my blood vessels. They only found a blood vessel abnormality in this small location in the left hemisphere of my brain. However, MRAs are not detailed enough to diagnose endothelial dysfunction. And like others here, I also have relatively low blood pressure (110/70). So you could be right about this blood vessel dysfunction. But what would be the cause of Generalized Endothelial Dysfunction?

Although I would like to note that I already tryed different anti-histamines including cetrizine but they didn't do much unfortunately.

  I'm not trying to suggest endothelial dysfunction is the cause of POIS. I was just suggesting that Zyrtec is a way of testing the theory of endothelial dysfunction. If cetirizine does not work, that may be evidence that the source of the problem is not mast cells opening the BBB. However, it takes a while for an injured or inflamed blood vessel to heal, similar to if you have a skin cut. It could take a week or more of consistent use to heal the injury. There are receptors other than H1 that can release arachidonic acid. So a better test might be using a general phospholipase inhibitor like the corticosteroid you suggested, Dexamethasone.

  I currently believe that the aneurysm in my brain is caused by white blood cell (lymphocyte, neutrophil) chemotaxis. And if there is a good reason for that chemotaxis, I don't want to interfere with it since my stack, though cumbersome, works for me.

  I know sometimes you refer to the herpes virus theory of POIS as my theory, but many people on this forum have suggested herpes as the cause of POIS even before I became a member. So I don't consider it my theory. Most of what I have been doing recently is summarizing the many ideas surrounding immunity and infection so that it is easy for us see the common points of agreements. Thanks for challenging the ideas and offering new ideas. We all beat POIS together! 

[Nas]

  I know sometimes you refer to the herpes virus theory of POIS as my theory, but many people on this forum have suggested herpes as the cause of POIS even before I became a member. So I don't consider it my theory. Most of what I have been doing recently is summarizing the many ideas surrounding immunity and infection so that it is easy for us see the common points of agreements. Thanks for challenging the ideas and offering new ideas. We all beat POIS together! 

No Nanna people 'hypothesized' about Herpes virus as a possible cause, on the other hand, you're the one who drew the the theory, and thus it is "your theory".
Same with me, I do not claim that I have an Endothelial theory. I claim to have a hypothesis that Endothelial dysfunction can be a possible cause and I'm asking members here to help me draw the theory.
Anyways full credit for your time and effort on the theory is where it's due.
Anyways I'm not challenging anything really I'm just too desperate to do nothing. Lol

[Quantum]

Hi Nas, and Nanni,

Just to add to this discussion, I would like to point out the role of cartilage/collagen in vascular integrity.   When there is a genetic problem with collagen quality/collagen metabolism in the body, veins are one of the structures that can be affected, because a blood vessel need a good and elastic wall in order to undergo dilatation, and than be able to contract back.   Varicose veins, as you may know, are veins in which the venous wall has been chronically enlarged and twisted, their wall have lost elasticity, and they do not go back to original size, leading to many physiological problems ( https://en.wikipedia.org/wiki/Varicose_veins).  However, I do not know if varicose veins can worsen endothelial dysfunction, but I figure out that it would.  The endothelium is lining the interior of the venous wall, so if the later is dilated, it automatically stretches the endothelium.  I suppose that stretching the endothelium can have a worsening effect on permeability problems.


In my own case, I clearly have a defect in collagen/cartilage genetic, as shown by a rib cage birth defect linked to a cartilage malformation.   Women in my family also have a high occurrence of varicose veins in the legs, and both my parents had severe hemorrhoids, which is also a problem of chronic venous dilatation.  I had hemorrhoids problems in the past, but I have learned to manage this, and no longer have them ( in particular, my ultra-healthy diet allows for soft stools and easy bowel movements, constipation being a main aggravating factor for hemorrhoids).   I also have some varicose veins on my body, mainly telangiectasis stage.  I have some dilated veins on the scrotum, in particular ( I work standing for many hours, and this may be the cause)   

Anybody here who had genetic test found has found defect for cartilage metabolism?

[nanna1]

Below is a screen shot from the paper ( eminal plasma components stimulate interleukin-8 and interleukin-10 release) that might be useful for looking into endothelial dysfunction. I talks about what happens when semen makes contact with certain cells in the blood and other tissues. And it also discusses the inflammatory and anti-inflammatory cytokines IL-8/IL-10.

  I do not have varicose. Neither my mom nor my dad has varicose veins. My aunts on my mom's side of the family do not have varicose veins. My veins are quite healthy looking. But I do have relatively low body weight, which allows me to see my veins more than people who have a higher percentage of fat. Also, my blood pressure is relatively low (110 systolic and 70 diastolic) like most athletes, but I am also physically active.

  I just wanted to suggest one thing to consider. If multiple people in the same family have POIS symptoms, is it possible that the cause of POIS is contagious? For example, if the cause of POIS can be transferred through saliva, then shouldn't the mother be able to pass it to a child who's immune system has not fully formed yet.

[Muon]

This article suggests: "Dexamethasone in doses of 8 to 40 mg per day upregulates angiopoietin 1 to stabilize the blood-brain barrier and downregulates VEGF" . What do you think? I'm not explicitly thrilled at trying a chorticosteriod but maybe worth a try?

Thanks for bringing this up Nas. It goes on my things to try list. I have no idea whether it may be worth it, I don't have the medical background to say anything useful about it in general. In my case however it could be of interest if the IL-8 production is of EC origin. At the end of the day it's a matter of experimentation. VEGF is by the way an interesting parameter to test in this context, there could be an overexpression of it. If you are going to use it Nas be careful not to suddenly abort intake schedules, ask your doctor.

My brother has elevated Lp-PLA2 outside of POIS episode. The immunologist made a comment next to it (it's in german):
''Erhohte Lipoprotein-assoziierte Phospholipase A2 (Lp-PLA2) Aktivitat. Dieses spricht fur eine erhohte endotheliale Entzundung''.
This could be an indication of endothelial inflammation. (the above sentence needs umlaut symbols but dunno how to insert them)

I currently believe that the aneurysm in my brain is caused by white blood cell (lymphocyte, neutrophil) chemotaxis.

Now to think of it, I had a conversation with Disaster about Sjogren's syndrome and IgG antibodies. He said he had an focus score of 1.0 which is a borderline criteria for lymphocyte infiltration near salivary glands in sjogren's. There could be chemotaxis at work here.
http://poiscenter.com/forums/index.php?topic=305.15

Just to add to this discussion, I would like to point out the role of cartilage/collagen in vascular integrity.

Good point. There are also indications of a link between mast cell disorders and cartilage/collagen disorders.

In my own case, I clearly have a defect in collagen/cartilage genetic, as shown by a rib cage birth defect linked to a cartilage malformation.

You mean like this: http://pectusexcavatumfix.com/wp-content/uploads/2015/06/My-Flared-Ribs-Case.jpg
My brother has this malformation, do you have something similar like this?

[Nas]

Just an update on Dexamethasone,
The article suggested that Dexamethasone would be taken from doses of 8 to 40, this can only achieved by taking injections and I can not really take injections personally, because I do not know how to inject my self, so that is not possible unfortunately.
I will be taking 1mg of oral Dexamethasone tablets though until I find a way to up the dosage safely.
Any suggestions on a safe chorticosteroid that has the same effectiveness as Dexamethasone?
Especially when it comes to angiopoietin 1 upregulation.

[nanna1]

I currently believe that the aneurysm in my brain is caused by white blood cell (lymphocyte, neutrophil) chemotaxis.

Now to think of it, I had a conversation with Disaster about Sjogren's syndrome and IgG antibodies. He said he had an focus score of 1.0 which is a borderline criteria for lymphocyte infiltration near salivary glands in sjogren's. There could be chemotaxis at work here.
http://poiscenter.com/forums/index.php?topic=305.15

Thanks Muon for sharing, I think my autoimmune test rule out Sjogren's syndrome for me. But I am thinking of getting more blood test. So it has been interesting to read about those immunoglobulins.

Hi Nas, I put a list of phospholipase A2 inhibitors here (see "cytosolic phospholipase A2 (cPLA2) inhibitors:" section). The corticosteroid phospholipase A2 inhibitors are listed at the bottom of "Anti-herpes therapuedics".

[nanna1]

Hi Nas, and Nanni,

Just to add to this discussion, I would like to point out the role of cartilage/collagen in vascular integrity.   When there is a genetic problem with collagen quality/collagen metabolism in the body, veins are one of the structures that can be affected, because a blood vessel need a good and elastic wall in order to undergo dilatation, and than be able to contract back.   Varicose veins, as you may know, are veins in which the venous wall has been chronically enlarged and twisted, their wall have lost elasticity, and they do not go back to original size, leading to many physiological problems ( https://en.wikipedia.org/wiki/Varicose_veins).  However, I do not know if varicose veins can worsen endothelial dysfunction, but I figure out that it would.  The endothelium is lining the interior of the venous wall, so if the later is dilated, it automatically stretches the endothelium.  I suppose that stretching the endothelium can have a worsening effect on permeability problems.

That's interesting Quantum! I heard about UC-II collagen and I was thinking of trying it for my bad knees. Also, I used to have arthritis in graduate school. I think B vitamins and vitamin D3 fixed the arthritis. Not sure if that has anything to do with collagen defects.

There was a clinical trial for UC-II collagen:Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial

[Quantum]

Just to add to this discussion, I would like to point out the role of cartilage/collagen in vascular integrity.

Good point. There are also indications of a link between mast cell disorders and cartilage/collagen disorders.

In my own case, I clearly have a defect in collagen/cartilage genetic, as shown by a rib cage birth defect linked to a cartilage malformation.

You mean like this: http://pectusexcavatumfix.com/wp-content/uploads/2015/06/My-Flared-Ribs-Case.jpg
My brother has this malformation, do you have something similar like this?

Yes, I have a pectus excavatum.  The link with POIS is not clear, if one at all, except if endothelial dysfunction may be linked to a collagen defect, and linked to a mast cell activation syndrome. But, it is clear that all those with a pectus excavatum do not have POIS, and it is also very clear that all those with POIS do not have a pectus excavatum.

[Muon]

Indeed Quantum the link isn't clear but it's supsicious nonetheless. I have kyphosis+POIS, my brother has pectus excavatum plus POIS like you do. Bone malformations can be seen in mast cell disorders, if you look up papers you won't find group studies (except for osteoporosis) of them but they can be found in case reports.

Storage granules of endothelial cells (Weibel-palade bodies) might be of interest in testing:
https://en.wikipedia.org/wiki/Weibel%E2%80%93Palade_body

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways.
https://www.ncbi.nlm.nih.gov/pubmed/23609797

VEGF:
Vascular permeability factor: a unique regulator of blood vessel function.
https://www.ncbi.nlm.nih.gov/pubmed/1791186

VEGF induces hyperpermeability by a direct action on endothelial cells.
https://www.ncbi.nlm.nih.gov/pubmed/9612282

Endothelial cell inflammation:
https://www.ncbi.nlm.nih.gov/pubmed/25022461
https://www.ncbi.nlm.nih.gov/pubmed/29549630

Background info on endothelial cell functions, lining and gaps:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289273/

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.10333

[Nas]

Hey guys,
So it really hasn't been three days since I tried 1mg Dexamethasone. But tbh I'm a little bit worried for many things.

1) To start off I'm really worried that 1mg is not really enough of a dosage especially when the article suggested a dosage of 8 to 40 mg. I'm not sure if a 1mg will take longer to show effectiveness or not show any at all because it's not enough.
2) I'm also worried about the many side effects of Dexamethasone, especially for increased chance of infection, and it's effect on natural steroid hormones expression in the body long term.
3) I would like to test for Dexamethasone effectiveness as soon as possible to know weather it is effective against POIS or not. Yet I need professional help to administer that. This professional help unfortunately is hard to get, since I have to explain to him what is POIS first before delving into his administration of the dosage. So what is your suggestion? I'm thinking of trying 20mg Dexamethasone for a week but I can not inject my self. Perhaps drinking the injection solution can be an alternative?
Perhaps there is a less dangerous alternative to dexamethason that can still upregulate angiopoietin 1?
I'm looking for your suggtion and advise here guys, I really just want to test the angiopietin 1 upregulation but I can't really debunk it with certainty without professional administration.

[Quantum]

Hi Nas,

20mg of dexamethasone is a very high dose. You should find a doctor to guide you in that.  In addition, I am not sure a doctor would go with injections rather than with oral tablets of dexamethasone.

There is a report on the old NS forum about a member who had relief ( less severity and less duration of symptoms) with oral dexamethasone, in the range of a few mg, taken at the onset of POIS symptoms.

Also, here on the forum, you can find the report of a member who had some success with low dose of oral prednisone:  http://poiscenter.com/forums/index.php?topic=2488.msg21324#msg21324

Coricosteroids on a current basis are not good for the body.  A as needed dosage like those mention above are far more safe on the long run.   I hope you will discuss that with a health professional.

[FernandoPOIS]

Hi guys,
I agree that the amount of 20 mg is very high. Perhaps prednisolone may help, and there are still other corticosteroids with less potency and fewer side effects. According to my knowledge the cost benefit I will never try corticosteroids and benzodiazepines. I think we have other ways.