COVID-19 News: SARS-Cov-2 Could Be Indirectly Affecting Angpt-Tie 2 Signaling Causing Endothelial Dysfunction

COVID-19 News: In the ongoing battle against the COVID-19 pandemic, scientists and researchers worldwide are tirelessly working to unravel the complexities of the SARS-CoV-2 virus. Recent findings from De Montfort University in Leicester, United Kingdom, shed light on a potential link between COVID-19 severity and endothelial dysfunction. This COVID-19 News report delves into the multifaceted nature of the virus, exploring its impact on endothelial function, particularly focusing on the Angiopoietin/Tie 2 signaling pathway.


A schematic demonstrating the Angiopoietin 1 and 2 molecular signalling in a normal and abnormal vasculature. The binding of Angpt 1 and Tie 2 at junctional complexes receptor results in stimulation of PI3K/Akt, antiapoptotic protein, nitric oxide synthase 3 (eNOS) and that in turn promotes endothelial cell survival throughout normal vasculature. The inhibition of FKHR by Angpt1/Tie 2 receptor phosphorylation inhibits inflammatory molecules and support vascular stability. While, during the abnormal condition, the binding of Angpt 2 and Tie 2 result in pericyte loss, increased in inflammatory gene expression and vascular destabilisation.

Understanding Coronaviruses
Coronaviruses (CoVs) constitute a family of single-stranded RNA viruses known to cause respiratory and digestive diseases in both humans and animals. Categorized into four genera - Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus - these viruses have varying severity in humans. The severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the latest addition, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), all belong to the Betacoronavirus genus and elicit more severe symptoms like pneumonia.
 
Virion Composition of Coronaviruses
Coronaviruses exhibit a distinct structure with a diameter ranging from 80 to 120 nm. The viral particle is enveloped by lipid layers containing spike (S), envelope (E), nucleocapsid (N), and membrane (M) proteins. The spike protein is crucial for viral entry, binding to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells. The viral genome, one of the largest among RNA viruses, encodes various structural and non-structural proteins vital for replication and infection.
 
SARS-CoV-2 Infection: A Cascade of Cellular Events
SARS-CoV-2 primarily infects respiratory epithelial cells, including alveolar type 2 (AT2) cells, leading to severe respiratory disorders. The virus enters host cells by binding its spike protein to ACE2, followed by cleavage by cell surface proteases. The infection triggers a cascade of cellular responses, involving the Akt signaling pathway and the nuclear factor-kappa B (NFκB) transcription factor. While the host immune system attempts to counter the infection through interferons, SARS-CoV-2 has mechanisms to evade these responses, involving viral proteases and non-structural proteins.
 
The Role of Endothelium in the Human Body
The circulatory system compris es an intricate network of blood vessels, including arteries, veins, capillaries, and lymph vessels. Endothelial cells, lining the interior of blood vessels, play a pivotal role in maintaining vascular homeostasis. These cells regulate various processes such as coagulation, thrombosis, inflammatory responses, and blood vessel tone. The stability of endothelium depends on signaling mediators like nitric oxide, prostacyclins, and angiopoietins, with their proper balance crucial for vascular integrity.
 
Angiopoietin Family: Orchestrating Vascular Growth
The Angiopoietin family, consisting of Angiopoietin 1, 2, 3, and 4, are glycoproteins crucial for vascular development and angiogenesis. Among them, Angiopoietin 1 plays a significant role in promoting angiogenesis, vessel stability, and endothelial cell survival. Conversely, Angiopoietin 2 exhibits antagonist properties, inducing vascular permeability and destabilizing blood vessels. The balance between Angiopoietin 1 and 2 levels is crucial for vascular stability and is implicated in various diseases.
 
Angiopoietin/Tie 2 Signaling Pathway
The Tie receptors, Tie 1 and Tie 2, are part of the receptor tyrosine kinase family expressed on endothelial and hematopoietic cells. Tie 2, in particular, interacts with Angiopoietins, initiating a signaling cascade that regulates blood vessel stability and endothelial cell survival. The intricate balance between Angiopoietin 1 and 2 levels influences Tie 2 signaling and plays a role in various pathological conditions, including acute lung injury and atherosclerosis.
 
Endothelial Dysfunction in COVID-19: Unraveling the Puzzle
Post-mortem studies of COVID-19 patients have revealed a procoagulant state and microvascular damage, emphasizing the crucial role of endothelial dysfunction in the pathogenesis of SARS-CoV-2. The virus's ability to bind to ACE2, expressed on endothelial cells, triggers intense immune activation and cytokine storm, leading to endothelial cell damage. Although the direct infection of endothelial cells by SARS-CoV-2 is not fully understood, evidence suggests that neighboring cells, such as epithelial and vascular pericyte cells, may contribute to the inflammatory response and cytokine storm that leads to endothelial dysfunction.
 
Mechanisms of Endothelial Cell Damage
Several mechanisms contribute to endothelial cell damage during SARS-CoV-2 infection. Inflammatory cytokines, such as TNF-α and IL-6, upregulate Angiopoietin 2, inhibiting nitric oxide and activating NFκB. The resultant endothelial dysfunction leads to blood clotting, hyperpermeability, and lung inflammation. The downregulation of nitric oxide and the elevation of vasoconstrictors like angiotensin 2 further contribute to endothelial dysregulation. Enrichment of SARS-CoV-2 RNA has been observed in lung endothelial cells, suggesting a direct impact on these cells.
 
The Complex Interplay of Angiopoietin/Tie 2 Signaling in COVID-19
Studies have proposed that SARS-CoV-2 infection may indirectly affect the Angiopoietin/Tie 2 signaling pathway through inflammatory cytokine storms and the stimulation of a pro-thrombotic state. The delicate balance between Angiopoietin 1 and 2, crucial for vascular stability, may be disrupted during severe COVID-19. The upregulation of Angiopoietin 2 in response to SARS-CoV-2 infection has been associated with increased vascular inflammation, leakage, and severity of symptoms.
 
Conclusion: A Call for Further Research
Endothelial dysfunction emerges as a critical player in the intricate dance between SARS-CoV-2 and the human body. While evidence suggests a potential indirect impact of the virus on the Angiopoietin/Tie 2 signaling pathway, further research is imperative to unravel the molecular intricacies of this interaction. Understanding the mechanisms underlying endothelial dysfunction in COVID-19 is vital for developing targeted therapies and improving patient outcomes. As scientists continue to delve into the depths of the virus's impact on the vascular system, the quest for effective treatments and preventative measures remains a top priority in the global fight against COVID-19.
 
The study review was published on a preprint server.
https://www.preprints.org/manuscript/202402.0212/v1
 
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