VEGF - Vascular Endothelial Growth Factor

[Hutan]

By popular demand, a thread on VEGF, Vascular Endothelial Growth Factor. As the name suggests, it's involved in the growth of blood vessels, e.g. after wounding or hypoxia.

Vascular endothelial growth factor (VEGF, /vɛdʒˈɛf/), originally known as vascular permeability factor (VPF),[1] is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).

It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions.[2] Serum concentration of VEGF is high in bronchial asthma and diabetes mellitus.[3] VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. It can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the retina of the eye and other parts of the body. Drugs such as aflibercept, bevacizumab, ranibizumab, and pegaptanib can inhibit VEGF and control or slow those diseases.

In mammals, the VEGF family comprises five members: VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C and VEGF-D. The latter members were discovered after VEGF-A; before their discovery, VEGF-A was known as VEGF. A number of VEGF-related proteins encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F) have also been discovered.

VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.

In addition to binding to VEGFRs, VEGF binds to receptor complexes consisting of both neuropilins and VEGFRs. This receptor complex has increased VEGF signalling activity in endothelial cells (blood vessels).[12][24] Neuropilins (NRP) are pleiotropic receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes. For example, Class 3 semaphorins compete with VEGF165 for NRP binding and could therefore regulate VEGF-mediated angiogenesis.[25]

 

[Hutan]

VEGF-A production can be induced in a cell that is not receiving enough oxygen.[21] When a cell is deficient in oxygen, it produces HIF, hypoxia-inducible factor, a transcription factor. HIF stimulates the release of VEGF-A, among other functions (including modulation of erythropoiesis). Circulating VEGF-A then binds to VEGF receptors on endothelial cells, triggering a tyrosine kinase pathway leading to angiogenesis.

So, if a cell doesn't have enough oxygen, all other things being equal, it sends a signal that releases VEGF-A. VEGF-A binds to endothelial cells, triggering angiogenesis, the development of new blood vessels.

We have this paper related to this:
The Emerging Role of Pericyte-Derived Extracellular Vesicles in Vascular and Neurological Health 2022 Sharma et al


The development of new blood vessels and higher levels of endothelial permeability isn't always good. High levels of VEGF are associated with some diseases e.g. tumours, and in diabetic retinopathy.

 

[Hutan]

Ebola
Ebola virus disrupts the inner blood-retinal barrier by induction of vascular endothelial growth factor in pericytes 2023 Gao et al
Ebola virus particles have been found to stimulate pericytes to secrete VEGF, causing a weaker blood-retinal barrier. They give examples of viruses affecting the integrity of the vascular endothelium. They report that anti-VEGF medication can restore barrier function.

Covid and Long Covid
Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC), Patterson et al 2023
Patterson's team reported finding that VEGF levels reduced as symptoms of Long Covid reduced. That might just be a natural reduction of levels that were high during the Covid-19 infection and not related to reductions in post-Covid symptoms over time. More on this thread too.

Clinical and biochemical characteristics of people experiencing post-coronavirus disease 2019-related symptoms:... 2022 Alfadda et al. This team reported higher levels of VEGF in people reporting the greatest severity of post-Covid symptoms.

Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism 2022, Patel et al. This paper reported higher levels of various sorts of VEGF in people with Long Covid symptoms compared to healthy controls. However, they didn't have controls that had had Covid-19 but didn't have persistent symptoms. So, we don't know if the raised levels are just a product of a recent viral infection.


Gender differences
Sex differences in the blood-brain barrier: Implications for mental health, 2022, Dion-Albert et al
It is notes that VEGF increases during pregnancy, as there is a lot of blood vessel creation going on. Therefore, pregnancy might be a natural experiment if levels of VEGF are relevant to ME/CFS.

 

[Hutan]

Fibromyalgia
CGRP, VEGF, and Clinical Manifestations in Women with Fibromyalgia, 2022, Rus et al. That study looked at levels of VEGF in women with fibromyalgia; they did not find any differences from healthy controls.

Conversion disorder/motor FND
Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/[FND], 2021, van der Feltz-Cornelis et al. In this small sample, people with motor FND and a range of other symptoms had VEGF at the low end of the normal range.

VEGF-a is significantly lower, suggesting a lack of vascular and neuronal support.

 

[Hutan]

Exercise intolerance and ME/CFS
Rather than high levels, there are some papers suggesting that low levels of VEGF might be relevant to ME/CFS.

..effect of VEGF gene inactivation ... on muscle enzyme activity, capillary supply & endurance exercise, 2020, Breen et al
In mice.

These data suggest that deletion of VEGF signaling simultaneously in endothelial cells and myofibers, while reducing treadmill endurance and despite compensatory augmentation of glycolysis, is not required for muscle capillary maintenance. Reduced endurance remains unexplained, but may possibly be related to a role for VEGF in controlling perfusion of contracting muscle.

That thread has links to a couple of papers that found low levels of VEGF in ME/CFS. It might be worth making threads for them, to have a closer look.

There is other interesting discussion there, including a link to a paper suggesting that VEGF is protective against neurodegeneration.

 

[Hutan]

There's some relevant discussion here:
Snow Leopard's cornucopia of wonder!
Including this paper:
Beyond the Matrix: The Many Non-ECM Ligands for Integrins
Some pathogens can disrupt the VEGF mechanisms e.g. increasing vascular permeability for a given level of VEGF

Other pathogenic hantaviruses also bind and cause the dysregulation of β3 integrins, resulting in the blockade of endothelial cell migration [118], and the enhancement of vascular endothelial growth factor (VEGF)-mediated vascular permeability [119].

The impact of a certain level of VEGF depends on the integrins binding to it (so it probably won't be as simple as a straight line between VEGF levels and symptoms)

One therapeutic strategy involves inhibiting VEGF-VEGR binding through the targeting of VEGFRs with monoclonal antibodies [229]. However, this approach has not proven as effective as drug developers and clinicians envisioned [229,230]. One reason for this failure may be that VEGFRs are not the only membrane-bound receptor of VEGFs, as these growth factors are also known to bind integrins. Some VEGF isoforms are integrated into the extracellular matrix, where they bind α3β1, αVβ3, and other αV integrins to promote endothelial cell adhesion [132]. Interestingly, the solubility of VEGF ligands greatly effects the integrin response. Vlahakis et al. found that when α9β1 integrin binds immobilized VEGF-A, it induces the recruitment of VEGFR2 into macromolecular structures at the cell membrane [136]. This serves to permit endothelial cell adherence and migration on VEGF-A functionalized Petri dishes, and stimulates the phosphorylation of the downstream effectors paxillin and ERK [136]. In contrast, when soluble VEGF binds α9β1 integrin, paxillin is phosphorylated, but neither the phosphorylation of ERK nor the formation of VEGFR2 macromolecular complexes are induced [136]. Moreover, VEGF-A is not the only VEGF member to have these functions. VEGF-C and VEGF-D also bind α9β1 integrin, stimulating the phosphorylation of paxillin and ERK, while contributing to lymphangiogenesis [231]. Taken together, these findings suggest a VEGF-induced synergy between VEGFR and integrins. Therefore, it may be beneficial to co-target integrins when employing an anti-VEGF therapeutic strategy during cancer treatment.

 

[duncan]

@Hutan , that was very nice of you.

I think Vegf may be relevant as a marker because of the cognitive decline many of us experience. So I think in many of us we will show low Vegf, which is fairly remarkable. It also would explain the hypoxia and low body temps (i'm often less than 97F). If we can't replenish blood cells and capillaries etc that we need to, then our organ don't get the oxygen etc they need.

High Vegf is common. You see it in cancer and infections and a lot of very bad things. There's studies aplenty on it.

Not so for low Vegf. Much of the little that's known is about neurodegeneration. Some about cardio. Some about pulonary stuff. But mostly - if I can use that word - revolves around cognitive decline. And we know a bit about that. Maybe I'll set up a poll to see who of us has tested vegf, and which percent is low.

@Hutan, again, thank you for that.

 

[Hutan]

From a member, thank you for this:

According to a German laboratory called IMD Berlin, Bartonella are the only (currently) known bacteria to induce VEGF in infected cells.

Deepl translation from their pdf - attached below (page 2):

Differential diagnosis of Bartonellosis - the 2nd indication for VEGF determination in blood.

Elevated serum VEGF levels are a differential diagnostic indication of Bartonella henselae co-infection in patients with tick-borne diseases. Bartonella are aerobic gram-negative rod-shaped bacteria. The reservoir of Bartonella is the domestic cat. Transmission to humans occurs through scratch or bite wounds of infected cats, but also through ticks. In the acute infection stage, they induce cat scratch disease. In the chronic infection stage, they can induce permanent immune activations. There is much evidence that co-infection limits therapeutic success in patients with Lyme disease.

Elevated VEGF blood levels are an indication of infection

Bartonella is the only human pathogenic bacterium described to date that induces VEGF in the infected cells. Fig. 3 shows the mechanism why the induction of VEGF confers a survival advantage to the bacteria. The proliferating bartonellae induce an energy deficit in the affected cells, i.e., they trigger an ATP deficiency. This deficit would reduce the probability of survival not only for the cells but also for the bartonellae themselves. The induction of VEGF and the resulting improved blood flow and nutrient supply to the infected tissue leads to a survival advantage for the bartonellae and thus to pathogen persistence. Whether increased VEGF levels are also associated with greater resistance to therapy and whether therapeutic reduction of VEGF levels can accelerate the success of pathogen-specific therapies can be assumed, but remains to be confirmed by clinical studies.

- - - - - - - - -
IMD Berlin cite only one source for this (Kempf et al.)attached as a pdf (in German).
There is a thesis about this (also in German), which can be found here: https://edoc.ub.uni-muenchen.de/1697/1/Volkmann_Bettina.pdf

 

[duncan]

According to a German laboratory called IMD Berlin, Bartonella are the only (currently) known bacteria to induce VEGF in infected cells.

I use to have bartonella. I still may even though I now test negative. But bart tests are notoriously bad, and only check for a couple strains anyway. Knowledgable infectious disease doctors navigate this issue by looking at vegf values. If you've elevated vegf, bartonella gets thrown into the differential diagnosis mix.

This is why I've been repeatedly checked for elevated vegf. But instead I consistently come in low. When you start checking the implications for low vegf, you are going to see that little is known about it, but much of what is suggests neurodegeneration.

Incidently, you'll see elevate vegf in many cancers because of new blood vessels or whatever needed to feed tumors.

Angiogenisis isn't a problem here, but it likely is where low vegf is found, and that would explain hypoxia etc. Paradoxially, if I remember correctly, sometimes hypoxia will encourage angiogenesis. But obviously that is not always the case.

 

[Hutan]

I think Vegf may be relevant as a marker because of the cognitive decline many of us experience. So I think in many of us we will show low Vegf, which is fairly remarkable. It also would explain the hypoxia and low body temps (i'm often less than 97F). If we can't replenish blood cells and capillaries etc that we need to, then our organ don't get the oxygen etc they need.

Yes, VEGF certainly is a molecule that is involved with a number of the things that come up often in ME/CFS research and theories. It would be good to have a close look at the papers reporting low levels in ME/CFS (mentioned in post #5) to see how reliable they look.

It's a bit hard to make a coherent story as yet, with the reports of high levels in some relevant conditions such as Long Covid. As I mentioned, as @Snow Leopard I think has said, things may be more complicated, with it not being so much about VEGF levels, but how effective the molecules can be. That might require looking at integrins and other things.

It might even be as complicated as an ongoing battle with an intracellular pathogen that tries to increase VEGF in order to increase nutrient supply as hypothesised by IMD Berlin above, but where the host (i.e. us) dials down the VEGF (and turns on the itaconate shunt) to try to essentially starve the pathogen to keep it under control. Clearly, I'm just tossing ideas around.

Anyway, it's good to 'put faces to the names' of these molecules, to start to understand what they do and how they work, and have possibilities to look at. It can help us make better sense of new research and maybe allow us to connect the dots.

On Bartonella, I find it an interesting pathogen, I posted about it on PR. We might need a thread on that too.

 

[duncan]

On Bartonella, I find it an interesting pathogen, I posted about it on PR. We might need a thread on that too.

I seem to recall reading that the leading cause of disability among veterinarians is bartonella.

 

[SNT Gatchaman]

Just adding some more recent references to this thread —

VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients (2023, Angiogenesis)
Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function (2023)

CircRNA_06354 might promote early-onset preeclampsia in humans via hsa-miR-92a-3p/vascular endothelial growth factor-A (2023, Journal of Hypertension)
(hsa-miR-92a-3p was elevated in ME/CFS in this paper)

Slightly older —

Hypoxia: molecular pathophysiological mechanisms in human diseases (2022, Journal of Physiology and Biochemistry)
Circulating Levels of Ang/Tie2 and VEGF-a Pathway Mediators Are Associated with Clinical Severity, Endothelial Barrier Disruption and Coagulation Activation in COVID-19 (2021, Blood)

 

[forestglip]

New preprint:

S4ME thread: VEGFA Sex-Specific Signature is associated to long COVID Symptom Persistence (2025, Preprint: SSRN)

Methods. Proteomic expression analysis of 171 individuals, in two time points, with confirmed SARS-CoV-2 infection, including 133 long COVID patients from the deeply characterized COVICAT cohort, assessed 1,395 protein biomarkers using Olink® technology. Statistical analyses with linear mixed models examined protein expression changes, long COVID status, and sex-specific differences. Functional analysis included Gene Set Enrichment Analysis (GSEA) and protein–protein interaction (PPI) networks.

Findings. Findings revealed dysregulated chemokine signaling, complement activation, and viral reactivation, aligning with prior studies, and identified VEGFA overexpression in long COVID patients (effect size 0.322, SE = 0.098, p = 0.0013), along with sex-specific expression patterns. Network analysis detected 109 nodes and 274 edges, with VEGFA ranking highest across all centrality metrics.