Less severe endothelial injury and vascular pathway activation in SARS-CoV-2 Omicron variant compared to Alpha

COVID-19 pandemic represented an opportunity to study the relationship between viral infections and vascular damage, and how vaccination and new variants can profoundly change the clinical presentation of the disease. We studied hospitalized COVID-19 patients, mostly vaccinated and infected with SARS-CoV-2 Omicron variant, to characterize their endothelial involvement and compare it with the Alpha variant infection. Circulating endothelial cells and their ACE2 surface expression were quantified in fresh blood samples from Omicron-infected patients and controls. In parallel, proteomic profiling was performed on plasma from controls subjects and patients infected either with Omicron or Alpha variants. Finally, we evaluated endothelial toxicity and NF-κB activation in HUVECs exposed to control or patient serum. Our results shown that Omicron infection is associated with an inflammatory response leading to endothelial injury in vivo. Proteomic analysis revealed that both variants alter key vascular homeostasis proteins (IL-6, TRAIL-R2); however, the Alpha strain induces greater cytokine release and activates distinct pathways such as PARP1, Renin-Angiotensin System. Consistently, serum from Omicron-infected patients induced lower endothelial toxicity and reduced NF-κB activation compared to Alpha. Overall, our results suggests that the SARS-CoV-2 Alpha variant exerts more pronounced deleterious vascular effects, likely trough a sustaining "vasculoinflammatory" loop.