COVID-19 As An Endothelial Disease and Its Relationship to Vascular Endothelial Growth Factor (VEGF) and Iodide

Abstract

Recently, attention around COVID-19 has shifted from respiratory symptoms to endothelial and other symptoms. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2. SARS-CoV-2 is known to downregulate ACE2. Vascular endothelial growth factors (VEGFs) are considered a key factor in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). VEGF concentrations were observed to be significantly higher in both ICU and non-ICU COVID-19 patients than in healthy controls. Although VEGFs promote angiogenesis, neurogenesis and neuroprotection, they also induce vascular leakiness and permeability. ACE2 antagonizes VEGF-A to reduce vascular permeability during acute lung injury. Also in breast cancer cells, ACE2 downregulated the expression of VEGF-A. Since SARS-CoV-2 downregulates ACE2, it likely cancels the VEGF-A-antagonizing effect of ACE2, leading to upregulation of VEGF and thus increase of vascular permeability and aggravation of endothelial damage. VEGF might be upregulated also in normoxic conditions. Iodide is a VEGF modulator, increasing lymphatic system related VEGF-C/D expression while simultaneously suppressing endothelial cell related VEGF-A/B expression. It may thus revert VEGF-A/B increase caused by SARS-CoV-2 downregulation of ACE2. Protein kinase B (Akt) induces protective nitric oxide (NO) production in endothelial cells, including inhibition of thrombosis and platelet aggregation. In one study, excess iodide activated PI3K/Akt pathway. In addition, iodide was demonstrated to accumulate in upper airway secretions and inhibit viral infections by participating in a nonspecific, broad spectrum mechanism applicable to multiple types of viruses. Also, in a mouse model, iodide was observed to protect against ischemia-reperfusion injury, which may be relevant for e.g. COVID-19 associated acute limb ischemia. It has also been suggested that inorganic iodides act as antioxidants through an ancient direct mechanism. Recently, a computer simulation suggested that iodide may protect against SARS-CoV-2 directly by exhausting the electron donor property of the S protein by acting as a strong electron sink. There is initial evidence to warrant comprehensive clinical and basic research on the related pathways and possible benefits of iodide for treatment of COVID-19.