Sex-Specific Characteristics of the Microcirculation

SNT Gatchaman

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Authors: Virginia Huxley and Scott Kemp
Published: July 27 2018
DOI: 10.1007/978-3-319-77932-4_20
PubMed Central link
Chapter link (free access)
Full book link (pdf, paywall)

Abstract
The requirements of metabolizing tissue are both continuous and variable; accordingly, the microvasculature serving that tissue must be similarly dynamic. Just as it is recognized that males and females of the same species have differing metabolic requirements, is it not likely that the microvasculature serving these tissues will differ by sex? This section focusing on the constituents of the microcirculation identifies what is known presently about the role sex plays in matching metabolic demand with microvascular function and areas requiring additional study. Many of the identified sex differences are subtle and easily ignored. In the aggregate, though, they can profoundly alter phenotype, especially under stressful conditions including pregnancy, exercise, and disease states ranging from diabetes to heart failure. Although the features presently identified to “have sex” range from differences in growth, morphology, protein expression, and intracellular signaling, males and females alike achieve homeostasis, likely by different means. Studies of microvascular sexual dimorphism are also identifying age as an independent but interacting factor requiring additional attention. Overall, attempting to ignore either sex and/or age is inappropriate and will prevent the design and implementation of appropriate interventions to present, ameliorate, or correct microvascular dysfunction.

Conclusions (exert)
Obviously healthy males and females are in fluid homeostasis but how they achieve this state differs by sex. The major implication is that for a given stressor, the responses in males and females, and the resulting pathology should the stressor not be removed, are likely to differ.
 
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SNT Gatchaman

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Sexual Dimorphism in Capillary Function [selected points]

It was found that nitric oxide synthase blockade with L- NAME induced an increase in blood-brain barrier (BBB) permeability (Evans blue dye extravasation), in females, not in males.

Surgical cessation of ovarian function in adult female swine also results in loss of meningeal microvascular barrier to fluorescently labeled protein; replacement of estrogen in a pulsed dose (estrogen patches) restored barrier function (and changes in vessel architecture), whereas flat dose estrogen replacement was not effective.
 
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SNT Gatchaman

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Venules [selected points]
The majority of vascular volume resides in the venous component of the microvasculature, and fluid exchange occurs predominantly across the capillaries.

Female astronauts during space flight experience a greater shift of fluid out of the plasma space than men and following return to gravity experience greater orthostatic intolerance. In response to orthostatic stress, males compensate by changing vascular resistance (microvascular), while females change heart rate.

It is in the venules draining the capillary tree that the majority of white blood cell/ endothelial cell (WBC/EC) interactions are observed, and it is in these vessels, with their lower hydrostatic pressure and relatively low flow rates, that increases in vascular leakage to proteins as well as white cell diapedesis are observed. Venules are also the site of integrin expression by EC in response to cytokines that promote WBC/EC interactions. In turn, inflammatory cytokine action is sensitive to the presence of estrogen and testosterone, respectively.
 
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SNT Gatchaman

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Vascular Reactivity (VSM Dilation/Constriction) [selected points]
Sex plays a role in pressure-induced myogenic constriction of arterioles. The myogenic response in arterioles from female rats, for example, is smaller than that of males. It was suggested an increased release of NO and/or elevated eNOS activity related to the higher levels of estrogen in the female animals could account for the reduction in myogenic response.

At the level of the mesenteric microvasculature, though, arteriolar reactivity, while reduced in males, remained unchanged by CH in females; eNOS protein expression in these vessels was unchanged although EC calcium was elevated in CH females compared to controls. This example illustrates that because one parameter, in this case total peripheral resistance, is sex-independent, it is incorrect to assume that all parameters are likewise independent of sex.

Only recently it has become accepted that coronary heart disease (CHD) and its manifestations differ by sex. Heart disease generally shows up at an earlier age in men than women. In human females, CHD is a microvascular disease which manifests by increased arteriolar constriction and vasospasm not generally found in males. In contrast, CHD in males is a macrovascular disease characterized by the presence of coronary occlusion and deposition of plaque.

In the gut, responses to ischemia/reperfusion injury differ by sex.

In male mice, 30 min of ischemia followed by 90 min of reperfusion was characterized by a loss of intestinal epithelial barrier integrity that paralleled increased endothelial/leukocyte interactions and reduction in blood flow resulting from a reduction in flow rate and the number of capillaries perfused. In females subjected to the same treatment, while loss of epithelial barrier function occurred, it was later in time.

Recent work has shown cerebral blood flow to be higher in young women than men, a difference not found in older adults. Similarly, in younger women, the response to hypercapnia was greater than in age-matched males; following menopause this sex difference was no longer present. An important consideration pointed out by Barnes is that when sex differences in MAP and vascular architecture are considered along with the differences in responses to hypercapnia, cerebral blood flow in young women is actually lower than age-matched men.

In addition to the anatomical differences, sexual dimorphism exists with respect to the mediators of microvascular tone.

A component that has been studied more intensely with respect to sex differences in blood pressure control is the autonomic nervous system.

These studies are germane to microvascular, particularly arteriolar, function, given that sympathetic tone (including muscle sympathetic nerve activity) influences VSM contractile state via alpha-adrenergic receptor activation to increase peripheral vascular resistance.

alpha-adrenergic vasoconstriction is lower in young females than males

the autonomic nervous system becomes a greater controller of blood pressure in females postmenopause.
 

SNT Gatchaman

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Posted for discussion on potential aetiologies of ME/CFS predicated on micro-thrombi (as found with Long Covid studies) and disturbance of micro-circulation function. Any theory of ME/CFS onset and maintenance needs to account for the established sex differences.
 

Pyrrhus

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Thanks so much for posting, and for sharing these enlightening excerpts from the chapter with those of us who don't have free access!

It was found that nitric oxide synthase blockade with L- NAME induced an increase in blood-brain barrier (BBB) permeability (Evans blue dye extravasation), in females, not in males.

Surgical cessation of ovarian function in adult female swine also results in loss of meningeal microvascular barrier to fluorescently labeled protein; replacement of estrogen in a pulsed dose (estrogen patches) restored barrier function (and changes in vessel architecture), whereas flat dose estrogen replacement was not effective.
Very interesting. The effect of estrogen on the permeability of the blood-brain-barrier (BBB) is certainly an important variable to keep in mind.

Female astronauts during space flight experience a greater shift of fluid out of the plasma space than men and following return to gravity experience greater orthostatic intolerance. In response to orthostatic stress, males compensate by changing vascular resistance (microvascular), while females change heart rate.
If "males compensate by changing vascular resistance (microvascular), while females change heart rate", then should we expect more women with ME to have tachycardia (POTS) with their orthostatic intolerance, while men might not have tachycardia with their orthostatic intolerance?

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Pyrrhus

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Vascular Reactivity (VSM Dilation/Constriction) [selected points]
These studies are germane to microvascular, particularly arteriolar, function, given that sympathetic tone (including muscle sympathetic nerve activity) influences VSM contractile state via alpha-adrenergic receptor activation to increase peripheral vascular resistance.

For those interested in the body's use of alpha-adrenergic and beta-adrenergic receptors in the autonomic system:

Wikipedia said:
α receptors
α receptors have actions in common, but also individual effects. Common (or still receptor unspecified) actions include:
[...]
Actions of the α2 receptor include:
[...]
  • negative feedback in the neuronal synapses - presynaptic inhibition of norepinephrine release in CNS
  • increased platelet aggregation (increased blood clotting tendency)
  • decreases peripheral vascular resistance
[...]
β receptors
[...]
Actions of the β1 receptor include:
[...]
Actions of the β2 receptor include:
  • smooth muscle relaxation throughout many areas of the body, e.g. in bronchi (bronchodilation, see salbutamol),[19] GI tract (decreased motility), veins (vasodilation of blood vessels), especially those to skeletal muscle (although this vasodilator effect of norepinephrine is relatively minor and overwhelmed by α adrenoceptor-mediated vasoconstriction)[24]
  • [...]
  • dilate arteries to skeletal muscle
  • [...]
  • inhibit histamine-release from mast cells
  • involved in brain - immune communication[30]
 

SNT Gatchaman

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Thanks so much for posting, and for sharing these enlightening excerpts from the chapter with those of us who don't have free access!
Oops didn’t realise my privilege there, my laptop must be valid, my iPad isn’t! I’ve edited the initial post to clarify. Not sure how much I’d be allowed to quote… perhaps individual threads could have a decent verbatim chunk?

EDIT: found better links and the standalone micro-circulation chapter appears to be public access. Updated post 1. Hopefully good now.
 
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nerd

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changing vascular resistance (microvascular)
If the males were healthy, this might be applicable. But as far as we know, the microvascular regulation is defective, isn't it? I think it might be because of TLRMs, just as Wirth and Scheibenbogen suspect, but I'm not through all relevant papers. There's definitely a link between RBCs, microvasculature, TLRM homeostasis, and peripheral hypoperfusion.

I can't tell yet. Some researchers suspect that there's too much vasoconstriction. However, the opposite might also be the case because too much vasodilation leads to more clotting and this leads to microvascular issues, hypoperfusion as well. Or it might just be poor regulation from different key players in that one system has to compensate for another dysfunctional one (e.g. the adrenergic/autonomic signaling), which leads to a dysbalance in vasoconstriction in macro- and microvasculature.

The real question is if this is just a downstream element which in itself works physiologically, or if there is a pathological mechanism in it.
 

SNT Gatchaman

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If "males compensate by changing vascular resistance (microvascular), while females change heart rate", then should we expect more women with ME to have tachycardia (POTS) with their orthostatic intolerance, while men might not have tachycardia with their orthostatic intolerance?
‘Yes that was what I was thinking. When I turned up to the cardiologist he chuckled (we had warm collegial rapport) and said I wasn’t the typical demographic. He said I should be a young female healthcare worker. I replied “will you grant 2 out of 3?”
 

SNT Gatchaman

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The real question is if this is just a downstream element which in itself works physiologically, or if there is a pathological mechanism in it.
If it were primary pathological, the genetic predisposition might hinge on the absolute diameter of capillary lumens. The distribution of smaller capillaries (whole body, muscle, gut, brain, peripheral nerves etc) could account for the symptom range.

Perhaps this is how you get “ME”, “POTS’‘, “fibromyalgia”, “iritable bowel syndrome”, “MCAS”?
 

Pyrrhus

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I think it might be because of TLRMs
What does TLRM stand for? :monocle:

Some researchers suspect that there's too much vasoconstriction. However, the opposite might also be the case
It might be a bit too simplistic to think of just vasoconstriction vs. vasodilation, as either one can lead to impaired circulation. The most solid models I have seen emphasize a lack of constriction of the veins, where such constriction would have been necessary to return blood to the heart. Therefore, the lack of constriction of the veins leads to impaired circulation in these models.

The real question is if this is just a downstream element which in itself works physiologically, or if there is a pathological mechanism in it.
To put it another way: is the impaired circulation just due to dysautonomic control of blood vessels, or is there something else going on? :monocle:
 

Pyrrhus

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Any theory of ME/CFS onset and maintenance needs to account for the established sex differences.
Excellent point. A related discussion:

Another example of a leaky blood-brain-barrier occurs in menstruation.
Right before, and during menstruation, the lower level of estrogen causes the blood-brain-barrier to become slightly more permeable. Some have speculated that this might contribute to pre-menstrual syndrome.
For what it's worth, here is a paper that briefly discusses pre-menstrual symptoms and ME:

Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Chu et al., 2019)
https://forums.phoenixrising.me/thr...hronic-fatigue-syndrome-chu-et-al-2019.84716/
Although women have discussed amongst themselves premenstrual aggravation of their ME/CFS symptoms for many years, only one other study besides ours has formally surveyed patients. Sixty-seven percent of Clark et al.'s (41) subjects reported worsening of ME/CFS before their periods, close to our figure of 53% (Figure 1).
 

SlamDancin

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I’m having some interesting effects with Aspirin/Nattokinase. Six days in now and the it’s having both positive and negative effects. I can report that baseline energy and my daytime need to be flat in bed seem to be decreased. It does seem to be having some alleviation of classic ME symptoms including the profound need to be flat and the heavy brain fog. On the negative side, I feel like I’m having what I imagine to be a die-off reaction of whatever pathogens have developed biofilm defenses in the circulatory system. It’s a slightly different form of fatigue but it comes with less of a feeling of being hit by a truck like ME fatigue and more of a warm forehead flu-like malaise. This has come with some increased anxiety and desire to be hidden away in bed in my room. Also it has seemed to increase heart palpitations and has made breathing slightly harder and more shallow and quick. Overall, it has affected my ME fatigue in a way that I would like to push through the bad to see if there is something to this protocol on a slightly longer course. I am pretty tuned into my ME symptoms and am a pretty good judge of the effects of treatments thereof. I saw on another forum that Dr Johnathan Edwards has his doubts about the microclotting pathology causing ME symptoms but from my short self experiment they do seem to be affected by Apsirin/Nattokinase. I will continue to check in with you guys and while I have the energy and lessened brain fog I just wanted to thank everyone on this thread for the service you guys do by bringing these discussions to the forum and helping to digest the science which is way over my uneducated head. Peace
 

SlamDancin

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@wabi-sabi Yeah it’s a bit concerning. I think I will drop the Aspirin as it may be too much blood thinning with the combo. Just did a short walk for exercise and although I felt light headed and cut it very short I do feel like perfusion is happening better than usual. Just being up for going for a walk is new relative to how I’ve been recently. But yeah can’t say I’d recommend the combo protocol because of those side effects