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

Avolio, Elisa; Carrabba, Michele; Milligan, Rachel; Williamson, Maia Kavanagh; Beltrami, Antonio Paolo; Gupta, Kapil; Elvers, Karen T; Gamez, Monica; Foster, Rebecca R.; Gillespie, Kathleen M.; Hamilton, Fergus; Arnold, David; Berger, Imre; Davidson, Andrew D.; Hill, David J.; Caputo, Massimo; Madeddu, Paolo

doi:10.1042/cs20210735

Cited by 117 publications

(138 citation statements)

References 60 publications

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“…Because the spike protein is the main immunogen in COVID-19 vaccines, the notion that immunization with spike could cause EC dysfunction should be discussed. In contrast to the spike protein levels [∼30 ng mL -1 ] found in severe COVID-19 ( 53 ), the circulating levels of the spike protein after an mRNA vaccine are minute [∼30 pg mL -1 ] ( 54 ), much lower than the EC 50 value of spike determined in this study [∼300 ng mL -1 ]. Furthermore, most of the spike remains attached to the cell surface and does not disperse much from the injection site ( 54 ).…”

Section: Discussioncontrasting

confidence: 80%

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Robles¹,

Zamora²,

Adán‐Castro

et al. 2022

Journal of Biological Chemistry

100

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Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNF⍺, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo , as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.

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Section: Discussioncontrasting

confidence: 80%

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Robles¹,

Zamora²,

Adán‐Castro

et al. 2022

Journal of Biological Chemistry

100

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“…The detection of the spike protein in brain endothelial cells has been associated with the formation of microthrombi, while the detection of pseudovirions (spike, envelope, and membrane proteins) without viral RNA in the endothelia of cerebral microvessels may theoretically cause microvascular injury irrespective of the immune response [ 26 , 27 ]. Furthermore, experimental data show the entrance of the spike protein in cardiac pericytes and pulmonary vascular cells, which promotes cell signaling leading to vascular cell dysfunction and cell growth/hypertrophy [ 28 , 29 ]. It seems extremely interesting to be able to detect spike protein levels in plasma [ 30 , 31 ], but to the best of our knowledge, no practical, clinical use has been implemented thus far while these techniques are not widely available for use to investigate whether there is an association between the observed changes in endothelial function and the spike levels in plasma [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

The effect of an mRNA vaccine against COVID-19 on endothelial function and arterial stiffness

et al. 2022

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To fight the COVID-19 pandemic, messenger RNA (mRNA) vaccines were the first to be adopted by vaccination programs worldwide. We sought to investigate the short-term effect of mRNA vaccine administration on endothelial function and arterial stiffness. Thirty-two participants (mean age 37 ± 8 years, 20 men) who received the BNT162b2 mRNA COVID-19 vaccine were studied in three sessions in a sequence-randomized, sham-controlled, assessor-blinded, crossover design. The primary outcome was endothelial function (assessed by brachial artery flow-mediated dilatation (FMD)), and the secondary outcomes were aortic stiffness (evaluated with carotid-femoral pulse wave velocity (PWV)) and inflammation (measured by high-sensitivity C-reactive protein (hsCRP) in blood samples). The outcomes were assessed prior to and at 8 h and 24 h after the 1st dose of vaccine and at 8 h, 24 h, and 48 h after the 2nd dose. There was an increase in hsCRP that was apparent at 24 h after both the 1st dose (−0.60 [95% confidence intervals [CI]: −1.60 to −0.20], p = 0.013) and the 2nd dose (maximum median difference at 48 h −6.60 [95% CI: −9.80 to −3.40], p < 0.001) compared to placebo. The vaccine did not change PWV. FMD remained unchanged during the 1st dose but decreased significantly by 1.5% (95% CI: 0.1% to 2.9%, p = 0.037) at 24 h after the 2nd dose. FMD values returned to baseline at 48 h. Our study shows that the mRNA vaccine causes a prominent increase in inflammatory markers, especially after the 2nd dose, and a transient deterioration of endothelial function at 24 h that returns to baseline at 48 h. These results confirm the short-term cardiovascular safety of the vaccine.

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“…The significance of CD147 in cancer progression has long been established [33][34][35], and recently, the role of CD147 in mediating vascular and immune complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has piqued the interest of numerous research teams [36][37][38]. However, the role of CD147 in the development of diabetic complications has received less attention, and most of the current research is based on observations from rodent models.…”

Section: Discussionmentioning

confidence: 99%

CD147 Levels in Blood and Adipose Tissues Correlate with Vascular Dysfunction in Obese Diabetic Adults

Ali

Mirza

Naquiallah

et al. 2021

JCDD

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CD147 is a glycoprotein that stimulates the production of matrix metalloproteinases (MMPs), known contributors to cardiovascular risk. The activity of CD147 protein depends on its glycosylation. However, it is unclear whether CD147 protein expression or glycosylation are influenced by the diabetic milieu characterized by hyperglycemia and abundant glycation-end-products (AGEs). We examined the circulating and visceral adipose tissue (VAT) levels of CD147 and their correlation with vascular function in obese, obese diabetic, and non-obese controls (n = 40, each). The circulating levels of CD147 and the glycosylated CD147 protein in VAT were considerably higher in obese, particularly obese diabetic subjects compared to controls. Obese diabetics had the lowest brachial and arteriolar vasoreactivity and the highest carotid pulse-wave velocity (PWV, a measure of arterial stiffness) among the three groups. CD147 correlated positively with body mass index (BMI), total and visceral fat mass, PWV, and plasma levels of glucose, insulin, MMPs, and AGEs and negatively with brachial artery and VAT-arteriolar vasoreactivity and nitric oxide production. Multivariate regression revealed that BMI, body fat mass, insulin, and glucose levels significantly predicted CD147. Our data suggest that higher levels of CD147 in obese subjects, particularly those with diabetes, are linked to vascular dysfunction and several cardiometabolic risk factors.

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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

Cited by 117 publications

References 60 publications

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

The effect of an mRNA vaccine against COVID-19 on endothelial function and arterial stiffness

CD147 Levels in Blood and Adipose Tissues Correlate with Vascular Dysfunction in Obese Diabetic Adults

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