ABSTRACT
Endothelial dysfunction and inflammation contribute to the vascular pathology of Coronavirus Disease 2019 (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells and thus inflammation may be better explained as secondary responses to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive SARS-CoV-2 infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2 infected lung alveolar epithelial cells. We found that ACE2 and TMPRSS2 mRNA expression in lung vascular cells including primary human lung microvascular endothelial cells (HLMVEC), pericytes, smooth muscle cells and fibroblasts was 20-90-fold lower compared to primary human alveolar epithelial type II (AT2) cells. Consistently, we found that HLMVEC and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVEC when exposed to conditioned medium from SARS-CoV-2 infected human ACE2 stably transfected A549 epithelial cells (hACE2-A549). Furthermore, we demonstrated that exposure of HLMVEC to conditioned medium from SARS-CoV-2 infected hACE2-A549 cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM1, VCAM1, IL-6 as well as complement components such as C3, C3AR1, C1QA and CFB. Taken together, our data support a model in which lung endothelial/vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).