Journal
EMBO MOLECULAR MEDICINE
Volume 14, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202114844
Keywords
COVID-19; GI symptoms; intestinal inflammation; vascular permeability; VEGF
Categories
Funding
- National Natural Science Foundation of China [81872113, 81870411, 82172241]
- National Key Research and Development Plan for the Emergency Management of Novel Coronavirus Pneumonia [2020YFC0842400]
- Special Project of Guangdong Science and Technology Department [2020B111113001]
- Science and Technology Program of Guangzhou [202008030001]
- Novel Coronavirus Epidemic Prevention and Control Emergency Project of Zhuhai City [ZH22036302200005PWC]
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SARS-CoV-2 infection can cause gastrointestinal symptoms, and plasma VEGF levels are correlated with disease severity. Animal models show that SARS-CoV-2 spike protein activates signaling pathways in intestinal cells to promote VEGF production, leading to increased intestinal permeability and inflammation.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can cause gastrointestinal (GI) symptoms that often correlate with the severity of COVID-19. Here, we explored the pathogenesis underlying the intestinal inflammation in COVID-19. Plasma VEGF level was particularly elevated in patients with GI symptoms and significantly correlated with intestinal edema and disease progression. Through an animal model mimicking intestinal inflammation upon stimulation with SARS-CoV-2 spike protein, we further revealed that VEGF was over-produced in the duodenum prior to its ascent in the circulation. Mechanistically, SARS-CoV-2 spike promoted VEGF production through activating the Ras-Raf-MEK-ERK signaling in enterocytes, but not in endothelium, and inducing permeability and inflammation. Blockage of the ERK/VEGF axis was able to rescue vascular permeability and alleviate intestinal inflammation in vivo. These findings provide a mechanistic explanation and therapeutic targets for the GI symptoms of COVID-19.
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