COVID-19 Is a Vascular Disease: Coronavirus’ Spike Protein Attacks Vascular System on a Cellular Level

SARS-CoV-2 Spike Protein Vascular Endothelial Cells

Representative images of vascular endothelial control cells (left) and cells treated with the SARS-CoV-2 Spike protein (right) show that the spike protein causes increased mitochondrial fragmentation in vascular cells. Credit: Salk Institute

Salk researchers and collaborators show how the protein damages cells, confirming COVID-19 as a primarily vascular disease.

Scientists have known for a while that SARS-CoV-2’s distinctive “spike” proteins help the virus infect its host by latching on to healthy cells. Now, a major new study shows that they also play a key role in the disease itself.

The paper, published on April 30, 2021, in Circulation Research, also shows conclusively that COVID-19 is a vascular disease, demonstrating exactly how the SARS-CoV-2 virus damages and attacks the vascular system on a cellular level. The findings help explain COVID-19’s wide variety of seemingly unconnected complications, and could open the door for new research into more effective therapies.

“A lot of people think of it as a respiratory disease, but it’s really a vascular disease,” says Assistant Research Professor Uri Manor, who is co-senior author of the study. “That could explain why some people have strokes, and why some people have issues in other parts of the body. The commonality between them is that they all have vascular underpinnings.”

Salk researchers collaborated with scientists at the University of California San Diego on the paper, including co-first author Jiao Zhang and co-senior author John Shyy, among others.

While the findings themselves aren’t entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time. There’s been a growing consensus that SARS-CoV-2 affects the vascular system, but exactly how it did so was not understood. Similarly, scientists studying other coronaviruses have long suspected that the spike protein contributed to damaging vascular endothelial cells, but this is the first time the process has been documented.

In the new study, the researchers created a “pseudovirus” that was surrounded by SARS-CoV-2 classic crown of spike proteins, but did not contain any actual virus. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model—proving that the spike protein alone was enough to cause disease. Tissue samples showed inflammation in endothelial cells lining the pulmonary artery walls.

The team then replicated this process in the lab, exposing healthy endothelial cells (which line arteries) to the spike protein. They showed that the spike protein damaged the cells by binding ACE2. This binding disrupted ACE2’s molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented.

Previous studies have shown a similar effect when cells were exposed to the SARS-CoV-2 virus, but this is the first study to show that the damage occurs when cells are exposed to the spike protein on its own.

“If you remove the replicating capabilities of the virus, it still has a major damaging effect on the vascular cells, simply by virtue of its ability to bind to this ACE2 receptor, the S protein receptor, now famous thanks to COVID,” Manor explains. “Further studies with mutant spike proteins will also provide new insight towards the infectivity and severity of mutant SARS CoV-2 viruses.”

The researchers next hope to take a closer look at the mechanism by which the disrupted ACE2 protein damages mitochondria and causes them to change shape.

Reference: “SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2” by Yuyang Lei, Jiao Zhang, Cara R. Schiavon, Ming He, Lili Chen, Hui Shen, Yichi Zhang, Qian Yin, Yoshitake Cho, Leonardo Andrade, Gerald S. Shadel, Mark Hepokoski, Ting Lei, Hongliang Wang, Jin Zhang, Jason X.-J. Yuan, Atul Malhotra, Uri Manor, Shengpeng Wang, Zu-Yi Yuan and John Y-J. Shyy, 31 March 2021, Circulation Research.
DOI: 10.1161/CIRCRESAHA.121.318902

Other authors on the study are Yuyang Lei and Zu-Yi Yuan of Jiaotong University in Xi’an, China; Cara R. Schiavon, Leonardo Andrade, and Gerald S. Shadel of Salk; Ming He, Hui Shen, Yichi Zhang, Yoshitake Cho, Mark Hepokoski, Jason X.-J. Yuan, Atul Malhotra, Jin Zhang of the University of California San Diego; Lili Chen, Qian Yin, Ting Lei, Hongliang Wang and Shengpeng Wang of Xi’an Jiatong University Health Science Center in Xi’an, China.

The research was supported by the National Institutes of Health, the National Natural Science Foundation of China, the Shaanxi Natural Science Fund, the National Key Research and Development Program, the First Affiliated Hospital of Xi’an Jiaotong University; and Xi’an Jiaotong University.


View Comments

  • Some one in the scientific community must comment on the joint sites of cooperation
    of the research and the varied nationality of the scientists working on the project!

  • And what about those many numbers in the total population who contract the virus, recover with seemingly little damage if any to their vascular system? Are their other unknown factors that give them natural immunity?

    • William, it's been known since early in the pandemic that maybe 50% of people are not susceptible (that is, who don't have visible symptoms). However, there seems to be no way to predict who that would be. Nor is it known if one can have no visible symptoms but still have blood related disease that is not visible, or perhaps is not recognized for years.

      • My assumption is that it depends on the number of virus particles the person receives within a certain period.
        If you get in a close contact with someone who has already contracted the virus and spend hours together (like in a hospital room or a small office) there's a high chance for both to replicate and exchange the virus back and forth more and more exponentially and overloading your bodies before their immune systems respond. An open space or just an open window could reduce the virus transmission. You walk in the park and an infected person coughs near you, so you manage to get few virus particles but keep walking and breathing fresh air. Those particles slowly replicate and start sending signals to your body's immune system, so it manages to prepare and respond to the infection before it takes you down or even disappear unnoticed.
        My other assumption is about the new virus variants: the ones that draw attention do not come from the second most populated country with very high population density - India, as it should be in theory. Most of them have appeared in countries with multiracial populations, though. The miscegenation seems to be the common factor for the number of new variants from South Africa, Brazil, United Kingdom and the United States. The mixed DNA from all races might have given the virus during its replication "a key" for better transmission to any race.

  • I'm wondering what this research implies about mRNA vaccines that stimulate the production of spike proteins. Would these vaccines not cause similar harm?

    • It would be nice for them to address it, but given millions vaccinated, apparently not

      • I feel like there are a lot of propagandists showing up in the comments here. They say things like “vaccines are perfectly safe” which everyone knows is a blatant lie. Vaccination is a calculated risk and with tried and true vaccines the risks are very rare, but no vaccine is “safe” in that deaths and injuries occur due to allergies, negligence and medical incompetence. Anyone who says there is “no risk” with vaccines is a liar, else why would all throughout history there have been huge billion-dollar payouts for vaccine deaths and injuries? That being said, most vaccines are essential for health but with these covid vaccines there has been a suspension of scepticism and government and corporate coercion that is extremely alarming.

    • To all those wondering if the MRNA vaccine produces the spike.

      1. the vaccine has an imprint (kind of like a foot print but not the foot) of the spike and an enzyme which your immune system's beta cells identify as an antigen it needs to examine.

      2. your beta cells then process and read the enzyme with the mrna of the spike to watch out for the foot that will cause all this damage.

      Unless the MRNA vaccine gets into one of your cells exactly while its splitting, past the cell wall, past the cell nucleus, guide its self into the exact spot it can attach its self to your cell's own RNA (when dividing)... its not going to cause any harm to your body. Even if breaks from the enzymes which tell your immune system not to get rid of the useless mrna the body will most likely just get rid of the mrna.

      Your beta cells in your immune system know better than to copy random mrna in the body. If the mrna wiggles free from the enzyme that stabilizes the mrna vaccine, the immune system will just eradicate the mrna anyways.

      You retards fell asleep in biology 101 of high school and it shows. You dumb asses also watched too much resident evil and think thats actual science and it shows.

      I hope in the future humanity will be a little smarter but seeing how the future is based off you, we are F-ed.

    • Cellular biology 101. Can not happen as this paper suggests. Spikes created inside cells from mRNA are degraded before they exit the cell through the MCH mechanism and the result it the standard immune system hand off is made to fully consume and degrade these protein peptides. Watch this

  • Is the 'spike' protein that allegedly attacks the vascular system the same one that the Pfizer mRNA vaccine stimulates the body to produce? -- asking for a concerned friend who took the vaccine.

    • The vaccine has a limited number of spike proteins, and since it's not part of a virus it cannot reproduce. The vaccine allows the body to recognize spike proteins so it can learn to fight them, without the risk of a virus that can replicate spike proteins to the point of killing a person.

      This explains why the vaccine can make you a little bit ill. If it's comforting, a little back-of-the-envelope math shows that people are at least 50,000 times more likely to die from covid than to get a serious complication from the vaccine.

      • How can you give the odds of someone dying of covid vs a vaccine like AstraZenica when you don’t even know their medical history or current medications?

      • Show the data which proves a healthy 10 year old is 50000 times more likely to die from covid 19 vs a vaccine. The majority of people wouldn't even know they had covid. Your mis-information is just as bad as some antivaxxers.

    • Even if it's turns out to be true that mRna spike proteins can harm your cells. (a pretty tall order) There is not enough of the viral matter in the vaccine to do significant harm without replication, which it cannot do.

  • These findings should be VERY WIDELY reported to help vaccine skeptics understand the risks they are taking with their own health and that of others.

    • I would argue the opposite. If spike proteins are dangerous, why do the vaccines produce them?

    • Yes, and that's why it can make you a little ill. But since it's not part of a virus, it cannot replicate. This gives your body the opportunity to learn how to fight it without the risk of the virus replicating so much that it does serious damage or kills you.

      • Covid makes most people “not ill at all” or “a little ill” as well. The point of the mRNA vaccines that you don’t *need* the virus itself there to replicate because the mRNA is there to be read and the spike protein is produced. The point of the article is that the spike protein is dangerous, so if the vaccine is producing spike proteins, it’s quite a leap in logic to say that the vaccine is “safe” (whatever definition that is today).

        • 'Covid makes most people “not ill at all” or “a little ill” as well.'
          No one knows that. Most people don't show symptoms, but no one knows how damaged they body get. Since many cardiovascular diseases are "silent killers", those people may have their vascular system very damaged and only show any health problem in the future.

    • Yes, that's why they induce vascular effects in some cases. Just like the virus.

  • I agree that if the mRNA vaccines themselves stimulate the human body's cells to produce spike proteins, shouldn't there be some concern that by this process the mRNA vaccines could ultimately cause the same vascular damage?

    • With mRNA vaccine technology the spike protein is made inside the cellular machinery, but it goes on to be destroyed once it is made inside the cells and CAN NOT EXIT the Cell intact.

  • Vaccines that trigger spike protein production only affect a very limited number of cells, as the genetic material that these vaccines contain does not auto-replicate in the body. In that way, these few cells are able to produce safe levels of spike protein, which are enough to trigger the intended immune response without any of the damaging effects. In contrast, the virus is able to produce many copies of itself in a very short time before the body can make any attempt to control it. This means that very large amounts of circulating spike proteins are produced, generating the adverse effects that the authors identified in their study. If you have access to any vaccine, please take it, they are all good to protect you and your loved ones.

  • The Pfizer/BioNTech and Moderna vaccines carry instructions to produce a variant of the spike protein that has been locked into what's called a "prefusion-stabilized conformation".

    Because the vaccine produced spike proteins are locked into this state, they cannot properly bind to the ACE2 receptors in other, healthy cells. This is because the normal spike protein must change its shape in order to achieve "fusion" with the ACE2 receptor.

    So the vaccines should be perfectly safe, even in light of this new information.

    • No vaccine is “perfectly safe.” It is a calculated risk. And the vaccines are in emergency use trials until 2023. Why can’t people sue pharmaceutical companies if they have disabling reactions or their family members die from it? If they are so safe, surely companies should have confidence in their products?

    • Binding occurs in the pre-fusion state. It is locked in the pre-fusion state to stabilize it not to prevent binding. The spike protein churned out by the body's cells in response to the mRNA contain a fully-functional s1 binding sub-unit and RBD. The pathogenecity of the S-protein was not yet realized until long after the so-called "vaccine" was created and released.

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