New evidence for T-cadherin COVID-19 pathogenesis, endothelial dysfunction, and lung fibrosis

Ekaterina Semina ^1,2 Vladimir Popov ¹ Nikita Khabibullin ³ Polina Klimovich ^1,4 Veronika Sysoeva ¹ Ella Kurilina ⁴ Zoya Tsokolaeva ⁴ Vsevolod Tkachuk ^1,4 Kseniya Rubina ^1*

• ¹ Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Moscow Oblast, Russia
• ² Institute of Medicine and Life Science, Immanuel Kant Baltic Federal University, Kaliningrad, Kaliningrad Oblast, Russia
• ³ Chumakov Federal Scientific Center for Research and Development of Immune-and- Biological Products (RAS), Moscow, Moscow Oblast, Russia
• ⁴ National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Moscow Oblast, Russia

The COVID-19 pandemic had an unprecedented impact on all aspects of human activity worldwide, frequently resulting in post-acute sequelae and affecting multiple organ systems. The underlying mechanisms driving both acute and post-acute manifestations of COVID-19 are still poorly understood, warranting further investigation for new targets. The study represents the first attempt to explore the role of T-cadherin in COVID-19 pathogenesis as well as its implications in pulmonary fibrosis and endothelial dysfunction. First, we revealed a significant decrease in T-cadherin expression in postmortem lung samples from COVID-19 patients. This down-regulated T-cadherin expression correlated with the elevated levels of VE-cadherin and reduced levels of β-catenin, suggesting a disruption in endothelial cell-cell contact integrity and function. Second, the reciprocal relation of T-cadherin and VE-cadherin expression was further confirmed using cultured human endothelial Ea.hy926 cells. Tcadherin overexpression caused a decrease in VE-cadherin mRNA expression in cultured endothelial cells providing additional evidence in favor of their interplay. Third, employing Cdh13-/-mice, we unveiled the protective role of T-cadherin deficiency against bleomycin-induced lung fibrosis. Fourth, we demonstrated the mice lacking T-cadherin to have down-regulated ROS production and Nox2 mRNA expression in an angiotensin II-mediated endothelial dysfunction model. Our findings provide rationale for further studies into T-cadherin-mediated mechanisms in these processes.