Relationship Between Endothelial and Angiogenesis Biomarkers Envisage Mortality in a Prospective Cohort of COVID-19 Patients Requiring Respiratory Support

Abstract

PurposeEndothelial damage and angiogenesis are fundamental elements of neovascularisation and fibrosis observed in patients with coronavirus disease 2019 (COVID-19). Here, we aimed to evaluate whether early endothelial and angiogenic biomarkers detection predicts mortality and major cardiovascular events in patients with COVID-19 requiring respiratory support.MethodsChanges in serum syndecan-1, thrombomodulin, and angiogenic factor concentrations were analysed during the first 24 h and 10 days after COVID-19 hospitalisation in patients with high-flow nasal oxygen or mechanical ventilation. Also, we performed an exploratory evaluation of the endothelial migration process induced by COVID-19 in the patients' serum using an endothelial cell culture model.ResultsIn 43 patients, mean syndecan-1 concentration was 40.96 ± 106.9 ng/mL with a 33.9% increase (49.96 ± 58.1 ng/mL) at day 10. Both increases were significant compared to healthy controls (Kruskal–Wallis p < 0.0001). We observed an increase in thrombomodulin, Angiopoietin-2, human vascular endothelial growth factor (VEGF), and human hepatocyte growth factor (HGF) concentrations during the first 24 h, with a decrease in human tissue inhibitor of metalloproteinases-2 (TIMP-2) that remained after 10 days. An increase in human Interleukin-8 (IL-8) on the 10th day accompanied by high HGF was also noted. The incidence of myocardial injury and pulmonary thromboembolism was 55.8 and 20%, respectively. The incidence of in-hospital deaths was 16.3%. Biomarkers showed differences in severity of COVID-19. Syndecan-1, human platelet-derived growth factor (PDGF), VEGF, and Ang-2 predicted mortality. A multiple logistic regression model with TIMP-2 and PDGF had positive and negative predictive powers of 80.9 and 70%, respectively, for mortality. None of the biomarkers predicted myocardial injury or pulmonary thromboembolism. A proteome profiler array found changes in concentration in a large number of biomarkers of angiogenesis and chemoattractants. Finally, the serum samples from COVID-19 patients increased cell migration compared to that from healthy individuals.ConclusionWe observed that early endothelial and angiogenic biomarkers predicted mortality in patients with COVID-19. Chemoattractants from patients with COVID-19 increase the migration of endothelial cells. Trials are needed for confirmation, as this poses a therapeutic target for SARS-CoV-2.

Proteomic profiling identifies biomarkers of COVID-19 severity

“…Furthermore, our data correlates with previous findings showing a COVID-19-specific elevation of inflammatory signaling pathways (Song et al, 2020a). SYND1 and EN-RAGE, markers associated with COVID-19 disease severity and mortality (Maldonado et al, 2022;Russell et al, 2022;Zeng et al, 2021;Zhang et al, 2021) were among the most significantly elevated markers in our severe cohort.…”

Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

“…Pathological vascularization and angiogenesis have been described as a unique comorbidity associated with SARS-CoV-2 infection in the pulmonary endothelium [ 108 ], including microvascular distortion and increased intussusceptive angiogenesis [ 109 , 110 ]. Moreover, VEGF, as well as other angiogenic-related analytes, were found to be increased in COVID-19 patients (including PTX3), which correlated with disease severity [ 111 ]. Accordingly, VEGF levels were 8% increased in the supernatants of SARS-CoV-2-exposed HBMECs, even though vegf transcripts remained unaltered.…”

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

“…Like other types of cell senescence, virus-induced senescence is associated with senescence-associated secretory phenotype (SASP), which is evidenced by increased secretion of pro-inflammatory cytokines, pro-coagulatory factors and VEGF. Elevated level of VEGF in senescent ECs and COVID-19 patients are potent trigger of increased angiogenesis in patient tissues, underlying the clinical utility of anti-VEGF treatment for COVID-19 patients [ 86 , 87 ]. The net effect of SARS-COV-2 infection induced senescence and angiogenesis is potentially dependent on stage of disease.…”