Timon Kuchler, Andrea Ribeiro, Maciej Lech, Javier Carbajo-Lozoya, Kristina Adorjan, Hans Christian Stubbe, Martina Seifert, Anna Wöhnle, Veronika Kessler, Johanna Negele, Uwe Heemann, Christoph Schmaderer
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引用次数: 0
Abstract
Background: SARS-CoV-2 infection may lead to Post-COVID Syndrome (PCS), characterized by debilitating symptoms like persistent fatigue, cardiovascular symptoms, and cognitive dysfunction. Persistent endothelial dysfunction (ED) is a potential driver of ongoing symptoms. Yet, the underlying biological mechanisms remain unclear. Methods: In this prospective observational study, we characterized 41 PCS patients and 24 healthy controls (HC, matched out of n=204, recruited before the pandemic) and investigated the effect of SARS-CoV-2 Spike protein 1 (S1) and plasma from PCS patients on human retinal endothelial cells (HREC). Results: Plasma samples from PCS patients exhibited significantly elevated erythropoietin, VEGF and MCP-1 alongside decreased IL-6 levels compared to HC. Low Haemoglobin and Haematocrit were negatively associated with PCS severity. VEGF levels were positively correlated with Anti-S1 IgG levels in patients and upregulated on mRNA level in HREC exposed to S1. Additionally, S1 exposure promoted ROS production and transiently activated HIF-1α in HREC. Persistent activation of HIF-2α by S1 led to disrupted endothelial integrity. HREC exposed to plasma from severely affected PCS patients showed increased ROS and compromised barrier function. Treatment with Belzutifan, a HIF-2α inhibitor, restored barrier integrity in HREC exposed to S1 or PCS-plasma. Conclusion: These findings suggest that HIF-2α-mediated ED in PCS might be a potential therapeutical target for Belzutifan.