For a “novel” human coronavirus, SARS-CoV2 has already acquired a complex history. What began as a two-way fight between a virus and the immune system quickly morphed into a three-way battle: virus, immunity, and vascular system. Two factors drove this development.
First, the discovery that severe cases of COVID-19 almost always resulted in vascular damage, most notably widespread microvascular thrombosis.1 And secondly, the realization that several of the key comorbidities are characterized by vascular dysfunction, namely:
In this short post, we’ll take a brief look at one important feature of the story: the endothelium. It turns out that the endothelium is the battleground where much of this triangulation — virus, immune system, and vascular system — is played out.
Friend or Foe? Immunity and Inflammation
As is well known, endothelial cells (ECs) play an essential role in many physiologic processes, including vascular barrier function, osmotic balance, vasomotor tone regulation, blood rheology and maintaining vascular homeostasis.1 While clinicians tend to associate endothelial health with cardiovascular health, including its involvement in inflammatory responses, most people do not think of ECs as immune cells. However, they have been shown to participate in both innate and adaptive immunity, in multiple ways reacting to extracellular environmental changes.2 Because of their location in every blood vessel of the body, they are among the first cells to interact with pathogens, especially in cases of systemic dissemination, so they function as a kind of early warning system.
ECs amplify the immune response by producing pro-inflammatory cytokines and chemokines, and they also induce cytokine production in the immune cells. Sometimes, they function as antigen presenting cells. The endothelium also mediates the trafficking of leukocytes and their attachment to, or passage through, the blood vessel wall to underlying cells.2
Of course, the immune system is a two-edged sword. Over-stimulated, it produces and sustains the inflammation implicated in a wide range of acute and chronic conditions. Here again the endothelium plays a significant part, generating a wide range of pro-inflammatory cytokines including several interleukin molecules.2 This can set off a vicious circle, damaging the endothelium and thereby stimulating further inflammation. Such a cycle may be occurring in serious cases of COVID-19, which is associated with elevated cytokines IL-6, IL-8 and TNFa,3 and at worst a fatal cytokine storm.
Most recently, attention has been drawn to the complement system, one of the oldest parts of the immune system, which provides the first response to an infection like SARS-CoV-2 and is important for clearing viruses from the body.
Again, overstimulation can turn a friend into a foe. It appears that the complement system can promote thrombosis in several ways. It can increase tissue factor activity both in the bloodstream and on the endothelial surface, and tissue factor is known to initiate the intrinsic coagulation cascade. The complement system may activate platelet aggregation, and reduce fibrinolysis. Finally, the complement system activates the membrane attack system (MAC), which leads to cell lysis and cell death, and this appears to encourage the ECs to secrete platelet adhesive von Willebrand factor. In fact, the complement system can directly activate the endothelium, leading to increased endothelial permeability and surface adhesion.
The entire process is more complex than this summary suggests. However, what research now suggests is that “crosstalk” among the complement system, the coagulation system, and the endothelium may be one of the causes of the extensive thrombosis seen in COVID-19.4,5
In a recent webinar, functional medicine practitioner Dr. Sam Yanuck underlined, with dramatic simplicity, the central role of oxygen in this story. As he pointed out at the beginning of his presentation, without oxygen nothing else in medical practice matters.
As a core component of the vascular system, the endothelium is essential for delivering oxygen to the tissues,6 and when it is compromised the result can be hypoxia. Hypoxia is well known to be a predictor of poor outcomes in COVID-19.7 As Dr. Yanuck pointed out, hypoxia triggers hypoxia-inducible factor 1-alpha (HIF1a), which activates NF-kB. The result is a vicious cycle in which NF-kB promotes inflammation, leading to further endothelial damage and deteriorating disease outcomes. Interestingly, hypoxia can also sustain an overreacting complement system.5
The endothelium is everywhere, lining all 60,000 miles of the vascular system. A compromised endothelium may give free reign to a virus that can spread throughout the body, as SARS-CoV2 appears to do. Damage to the ECs not only gives the virus easier access to almost every organ but also pours gas on an inflammation fire, and this may help explain its unexpected discovery in multiple locations of pathogenesis apart from the lungs.
A Clinical Priority: The Endothelial Glycocalyx
From a clinical perspective, the first and possibly most effective therapeutic intervention may be the endothelial glycocalyx (EGX), a gel-like covering of the entire luminal surface of the vascular endothelium. This is the structure that regulates coagulation, inflammation, leukocyte and platelet adhesion, and the permeability of the blood vessel wall.8
The EGX easily collapses in response to inflammation, and when it is damaged the integrity of the endothelium as a whole is compromised. Conversely, restoring the EGX helps protect and maintain endothelial function.
So what are the takeaways beyond the current focus on COVID-19? Here’s one way to see it. While the impact of the immune system on vascular health is widely understood, we also need to recognize that ECs themselves are “non-professional” immune cells.
When we focus on the vascular system, we should be mindful of its active participation in the body’s immune responses. This integrated perspective comes naturally to a systems biology approach, which is the hallmark of functional medicine.
- Pons, S., Fodil, S., Azoulay, E. et al. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care 24, 353 (2020).
- Mai J, Virtue A, Shen J, Wang H, Yang XF. An evolving new paradigm: endothelial cells--conditional innate immune cells. J Hematol Oncol. 2013;6:61. Published 2013 Aug 22. doi:10.1186/1756-8722-6-61
- Clare Bryce, Zachary Grimes, Elisabet Pujadas et al. Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience. medRxiv Preprint
- Alexander Fletcher-Sandersjöö, Bo-Michael Bellander, Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review. Thrombosis Research, 2020;194:36-41
- Marchetti M. COVID-19-drven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure. Ann Hematol. 2020;99(8):1701-1707. doi:10.1007/s00277-020-04138-8
- Al-Soudi, M.H. Kaaij, S.W. Tas. Endothelial cells: From innocent bystanders to active participants in immune responses, Autoimmunity Reviews, 2017;16(9):951-962.
- Kashani KB. Hypoxia in COVID-19: Sign of Severity or Cause for Poor Outcomes. Mayo Clin Proc. 2020;95(6):1094-1096. doi:10.1016/j.mayocp.2020.04.021
- Onur Yilmaz, Baris Afsar, Alberto Ortiz, Mehmet Kanbay. The role of endothelial glycocalyx in health and disease, Clinical Kidney Journal, 2019;12(5) October:611–619.