Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.
Highlights
Microvascular complications are frequent and harmful in patients with coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with up to 11% of those hospitalised in intensive care units having myocardial ischaemia or infarction [1,2,3,4]
We show for the first time that human cardiac PCs express the alternative receptor CD147 (Figure 1E,F)
ICC showed that PCs express the major SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) as well as transmembrane serine protease 2 (TMPRSS2), a coreceptor required for proteolytic activation of the S protein [20] (Figure 2C)
Summary
Microvascular complications are frequent and harmful in patients with coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with up to 11% of those hospitalised in intensive care units having myocardial ischaemia or infarction [1,2,3,4]. The link between the two conditions is not completely understood, especially in the light of the controversy about the capacity of the coronavirus to infect the vascular endothelium [6,7,8,9]. A reduction in the vascular coverage by PCs was documented in the heart and lungs of human patients with COVID-19, in the absence of capillary rarefaction, suggesting that SARS-CoV-2 may affect the microvasculature by targeting PCs [16,17]
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