Active Infection & Immunity

Role of VEGF-A Signalling in Sepsis Pathophysiology

Funder Wellcome Charity-funded
Recipient organisation University of Nottingham
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

Blood vessels in septic patients are flooded with a protein called VEGF-A, and this project will test whether blocking it could prevent the cardiovascular collapse that kills many of them. Sepsis kills millions worldwide, largely because it causes blood vessels to leak and the heart to fail. Doctors know that VEGF-A levels rise during sepsis, and higher levels track with worse outcomes. But no one has worked out exactly how VEGF-A signalling drives that damage, or whether drugs that block it—already used in cancer treatment—could help. This project fills that gap by watching VEGF-A signalling in real time inside endothelial cells, using engineered biosensors and bacterial toxins to mimic sepsis in the lab. If the work succeeds, it could reveal a clear molecular target for treating sepsis-related cardiovascular dysfunction. That would open the door to repurposing existing anti-VEGF-A drugs for septic patients, potentially saving lives without the decade-long wait for a new drug. The research also uses retrospective patient data to check whether people already on VEGF-blocking cancer therapies show different cardiovascular outcomes during sepsis—a direct test of the idea in humans.

View original technical description
The overall research goal is to explore the role vascular endothelial growth factor A (VEGF-A) plays in sepsis development, particularly concerning the cardiovascular dysfunction observed in sepsis. VEGF-A is a potent stimulator of angiogenesis with its inhibition an important mechanism in targeted anti- cancer treatments. Raised VEGF-A serum levels are observed in sepsis, with increased levels potentially associated with worse clinical outcomes. However, the pharmacological dynamics of VEGF-A signalling in sepsis remainsunclear. Initially the molecular pharmacology of VEGF-A signalling within endothelial cells will be monitored, this will be facilitated by calcium signalling assays along with using engineered NanoBiT-Technology. These methods will be used to monitor VEGF-A signalling dynamics in an endothelial sepsis like system, stimulated using the bacterial endotoxin Lipopolysaccharide (LPS) as the main inflammatory driver. This will be followed by the development of further physiologically relevant models including the introduction of donor derived PBMC’s in a co-culture method with endothelial cells, micro vessel development assays and ex vivo experimental approaches. This is aimed to investigate any direct cardiovascular benefits VEGF-A inhibition could provide in septic environments. Finally, we will use retrospective patient datasets to investigate if cardiovascular consequences are similarly altered in septic patients undergoing angiogenesis inhibiting treatments.

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Researchers

Benjamin Moore (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

VEGF signalling pathways in vascular permeability
Delineating a role for endothelium-derived C-type natriuretic peptide in the vascular and cardiac dysfunction associated with sepsis
The role of heterodimerisation between VEGFR-1 and VEGFR-2 in the regulation of vasculogenesis, angiogenesis and endothelial cell homeostasis
A VEGF-independent NRP1 mechanism for tissue vascularisation
The role of Lrg1 as a modulator of VEGF signalling in vascular endothelial cells

Original classification

PhD Studentship (Basic)

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