ABSTRACT
Background: The COVID19 disease has different outcomes ranging from asymptomatic disease to critically ill or even fatal outcomes in some people. This imposed the need for identification of early biomarkers that can predict the outcome. Previous studies show that VEGF-D has an important role in acute lung injury and acute respiratory distress syndrome, yet its role in COVID19 disease has not been evaluated thoroughly. Our study aimed to determine the possible use of VEGF-D as a predictor for COVID19 severity. Method(s): This is a retrospective study that includes 74 hospitalized patients with COVID19 in a period of one month at the University clinic for Infectious diseases and febrile conditions in Skopje. The patients were divided into two subgroups according to their outcome, a group of 45 patients with fatal outcome within the first week of hospitalization, and another group of 29 patients with mild COVID19 that required hospitalization less than 7 days without oxygen support. Sera samples were collected on the day of admission, and serological testing for human VEGF-D was performed using Quantikine ELISA Kit (R&D systems, Minneapolis, US). Result(s): The values measured for VEGF-D were 835.69+/-330.52 for the first group and 677.91+/-148.48 for the second. Student's t-test was performed, and it showed statistically significant difference between the groups;T test value = 2.413, p = 0.0183. The mean VEGF-D value in the group of patients with mild COVID19 is slightly above the reference range (153-642 pg/mL), while the group of patients with fatal outcome had significantly higher values. Conclusion(s): O ur f irst r esults i dentified V EGF-D a s a p ossible b iomarker for COVID19 severity. The significance of the test can be even of higher value, having in mind potential use of VEGF inhibitors as a treatment in COVID19 patients. The limitations of the study are the small sample size and variable time interval between symptom onset and hospital admission, so additional evaluation is planned on a larger cohort.
ABSTRACT
Disorders in pulmonary vascular integrity are a prominent feature in many lung diseases, including acute respiratory distress syndrome (ARDS), capillary leak syndrome, and COVID19. Paracrine signals are enriched in the lung and are critically important in regulating the homeostasis of the functional pulmonary microvasculature. Here, we employed single-cell RNA-sequencing (scRNAseq) to study ligand and receptor interactions in the native human lung microvascular niche, and identified soluble factors that are critical in endothelial integrity. The scRNAseq data reveals a total of 47 cell populations consisting of five vascular endothelial subtypes in human lungs, including general capillary EC, aerocyte capillary EC (EC aCap), arterial EC, pulmonary venous EC, and systemic venous EC. Using EC aCap as a signal receiving core (Receptors) and the putative adjacent cell types (alveolar fibroblast, ATI, ATII, pericyte, plasma cell, etc.) in the EC aCap niche as senders (Ligands), we identified that SLIT2-ROBO4, ANGPT1-TIE1, ADM-RAMP2, VEGFD-KDR, and BMP5-BMPR2 are the top specific and abundant pairs in the niche. Immunostaining and ELISA assays confirmed their spatial information and secretion level. Furthermore, upon treatment with these ligands, real-time resistance recorded using an electric cell-substrate impedance sensing (ECIS) system revealed that VEGFD, ANGPT1 (angiopoietin 1), and ADM (adrenomedullin) could markedly increase the electrical resistance of human lung microvascular, arterial, and venous endothelial cells, suggesting their strong impact on the endothelial barrier function. Deciphering the cell-cell soluble signals that improve endothelial integrity in human lungs lays the foundation for uncovering the pathogenesis of pulmonary vascular disorders and the development of ex vivo functional lung vasculature.