Hypertension, diabetes, and obesity are all strongly related to the severity of COVID-19 outcomes. COVID-19 also seems to involve systemic clotting as a major driver of severe outcomes (which I covered here, here, here, and here). A new preprint* released on May 12 suggests that these preexisting conditions predispose to clotting-driven COVID-19 severity by contributing to what could be called “leaky blood vessels.”
The inner lining of blood vessels is known as the endothelium, and is composed of endothelial cells that are joined together by junction proteins. These junctions prevent passage of substances between the cells, allowing the endothelial cells themselves to control the inflow and outflow of substances between the blood and the inside of the blood vessel wall.
These junctions aren't perfectly tight. For example, it is well established that LDL particles can move in and out of the endothelium between the cells, especially at branch points in the arteries where the permeability is higher. However, the average diameter of an LDL particle is 21 nanometers, and the average diameter of a SARS-CoV-2 virion is 82 nanometers, almost four times bigger. Variability in endothelial permeability is well known to play a role in how easily LDL particles pass into the blood vessel wall, so it is certainly plausible that it could play a role in how easily the much larger viral particles pass through.
Immediately underneath the endothelial cells are pericytes and vascular smooth muscle cells, which provide mechanical support and contribute to how dilated or constricted the blood vessels are. Other cells behind the endothelium include fibroblasts, which lay down collagen-rich tissue, and macrophages, which provide immune support and clean up junk.
In a healthful state, the blood mainly only comes in contact with the endothelial cells. In hypertension, diabetes, and obesity, the endothelial junctions are compromised and blood more easily reaches the cells behind the endothelium.
To determine which cells of the blood vessel wall can be infected by SARS-C0V-2, the coronavirus that causes COVID-19, the authors of the new preprint examined the RNA expression of ACE2 and various markers of cell type in mice and in previously collected data sets from human tissues.
Previous studies have suggested that ACE2 is expressed in endothelial cells, pericytes, fibroblasts, and macrophages. However, they found that examining endothelial cells for markers of pericytes revealed that endothelial cells positive for ACE2 were usually contaminated with pericytes. They also found a small population of apparently ACE2-positive fibroblasts in mouse brain, but they too turned out to be contaminated with pericytes. Other than this, they did not find ACE2 expressed in endothelial cells, fibroblasts, or macrophages.
In the vasculature of the mouse brain, and the heart from both mice and humans, they found ACE2 expression specific to the pericytes.
However, this was not true in the vasculature of the lung. Consistent with other studies, ACE2 in the lung was found in alveolar type 2 cells and in ciliated epithelial cells.
Pericytes did not express TMPRSS2, an enzyme needed to cleave the viral spike protein after it binds to ACE2 to allow the virus to fuse with the cell membrane. They did find that they express cathepsins B andL, however, which can substitute for TMPRSS2.
In mice, they experimentally inhibited the growth of pericytes to see how it would affect clotting risk. The mice lacking adequate pericytes developed spontaneous clotting, suggesting that pericytes establish a normal anti-clotting tone that restrains the pro-clotting activities of endothelial cells. In the absence of perictyes, the endothelial cells create a pro-clotting tone that leads to spontaneous clots.
Although they did not show specifically what SARS-CoV-2 does to pericytes, they established it as plausible that SARS-CoV-2, if it manages to pass between endothelial cells, could infect pericytes, and if this kills them or hurts their function, it could abolish their effects on the anti-clotting tone and lead to increased clotting.
My Thoughts On This Study
Given their conclusion that previous studies found ACE2 expression in other cell types of the blood vessel because they were contaminated with pericytes, I believe this study is likely to be controversial and scientists will have to duke it out a bit over their methodology before the conclusions are firm.
However, if the hypothesis put forth in this study is correct, it suggests several important things:
Exercise is critical. Shear stress (produced from the flow of blood parallel to the blood vessel wall) and nitric oxide decrease the permeability of the endothelium, and exercise increases both. This makes home exercise critical during lockdowns, and suggests that it should be absolutely top priority for policies to figure out how to make gyms essential businesses that can safely operate during lockdowns.
Citrulline at a dose such as 3 grams twice a day increases nitric oxide production.
Zinc and antioxidant protection are needed to stabilize the enzyme responsible for producing nitric oxide.
Reversing the disease states of hypertension, diabetes, and obesity is achievable over the medium- and long-term, but the bullet points above are achievable over the short-term. All of these strategies may be very important for preventing the clotting dysfunction of COVID-19 if the pericyte and “leaky blood vessel” hypothesis is confirmed.
Stay safe,
Chris
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Disclaimer
I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.