The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease

Clin Sci (Lond). 2021 Dec 22;135(24):2667-2689. doi: 10.1042/CS20210735.


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.

Keywords: CD147; COVID-19; Microvascular disease; Spike protein; angiotensin converting enzyme 2; pericyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Basigin / metabolism*
  • COVID-19 / blood
  • Caco-2 Cells
  • Cell Death
  • Child
  • Child, Preschool
  • Cytokines / metabolism
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Myocardium / cytology
  • Myocardium / enzymology*
  • Pericytes / enzymology*
  • Pericytes / virology
  • Primary Cell Culture
  • SARS-CoV-2 / physiology*
  • Spike Glycoprotein, Coronavirus / blood*
  • Young Adult


  • BSG protein, human
  • Cytokines
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Basigin
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2