COVID-19 triggers pulmonary tumor outgrowth through hypoxia- and inflammation-induced VEGF-dependent angiogenesis

Pulmonary nodules are highly prevalent in adult human populations, with a substantial proportion representing dormant cancerous lesions. We hypothesized that these pulmonary dormant cancers debilitate in growth owing to the lack of an angiogenic switch in tumors. In this study, we comprehensively investigated the hypothesis that specific pathological triggers can activate this angiogenic switch utilizing severe acute respiratory coronavirus 2 (SARS-CoV-2) infection-induced hypoxia as a primary physiological stimulus. Our findings provide compelling experimental evidence demonstrating that SARS-CoV-2 infection induces profound pulmonary hypoxia and severe tissue inflammation in animal models. This microenvironmental disruption markedly upregulates the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) within lung tissues. The resulting hyperactivation of the downstream VEGF-VEGFR2 signaling pathway effectively drives robust pulmonary neovascularization, a phenomenon frequently documented in clinical observations of COVID-19 patients.