Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects?

Abstract

Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage. A few studies suggest that serum VEGF-A may also be a potential biomarker for long COVID-19, whereas evidence for COVID-19 vaccines is lacking and merits further investigation.

Keywords: COVID-19 vaccine; NRP-1; SARS-CoV-2; VEGF-A; long COVID-19; post-COVID-19; small fiber neuropathy; spike protein.

Figure 1

Physiological pathways directed by the NRP/VEGF complex in vessels and nervous system. Blood vessels, lymphatic vessels, and the nervous system express VEGF-Rs and NRPs, both of which function as receptors for VEGFs. Angiogenesis and vasodilation are the final effects of the interaction between VEGF-A/VEGF-B and the receptor complex VEGF-R1/VEGF-R2–NRP-1 in blood vessels. VEGF-C and VEGF-D instead bind to the VEGF-R3–NRP-2 receptor complex in lymphatic vessels, which may lead to lymphangiogenesis and chemotaxis of leukocytes. Finally, VEGF-A can control neurogenesis and nociception by binding to the receptor complex VEGF-R2–NRP-1 in the nervous system. Nerve fibers may in turn release VEGF-A, which has paracrine effects on receptors expressed on patterned vessels. Abbreviations: NRP: neuropilin; VEGF: vascular endothelial growth factor; VEGF-R: vascular endothelial growth factor receptor. Created with BioRender.com.

Figure 2

The potential contribution of NRP-1 to human disease. Overexpression of NRP-1 in different clinical contexts may play either a protective or a pathogenic role. In cancer, the receptor may contribute to malignant cell proliferation and metastasis. Conversely, when upregulated in the nervous system, NRP-1 would prevent neuronal dysfunction, inflammation, and demyelination. When expressed on cardiomyocytes and vascular smooth muscle cells, NRP-1 could counteract cardiac hypertrophy and regulate vascular tone. Abbreviations: ADMA: asymmetric dimethylarginine; NRP-1: neuropilin-1. Created with BioRender.com.

Figure 3

Hypothetical cascade of events triggered by SARS-CoV-2 S protein leading to overproduction of VEGF-A. The S protein produced by the virus during infection or used for vaccine immunization may induce the upregulation of VEGF-A in several ways. SARS-CoV-2 infection of pulmonary alveoli may result in hypoxia and local hyperexpression of HIF-1α, which is a potent trigger for VEGF-A release. Furthermore, during COVID-19 and following vaccination, the S protein can activate both the innate and acquired immune response, with the final secretion of cytokines from monocyte/macrophages. This event may be enhanced by the binding of anti-spike antibodies to the FcRs of these cells. The release of proinflammatory cytokines may further contribute to the increase in VEGF-A levels. Additionally, it may be supposed that the S protein may bind to NRP-1 in endothelial cells and destabilize the NRP-1/VEGF-R2 receptor complex, eventually preventing the docking to the endogenous ligand VEGF-A. Unbounded VEGF-A could be diverted to VEGF-R1 expressed on immune cells, amplifying the inflammatory background. Abbreviations: APC: antigen-presenting cell; COVID-19: coronavirus disease-19; HIF-1α: hypoxia-inducible factor 1α; NRP-1: neuropilin-1; VEGF-A: vascular endothelial growth factor A; VEGF-R1: vascular endothelial growth factor receptor 1; VEGF-R2: vascular endothelial growth factor receptor 2. Created with BioRender.com.