Vascular Endothelial Growth Factor

This page contains educational material about Chronic Inflammatory Response Syndrome due to water damaged building (CIRS). This is a biotoxin illness is that is caused by mold. Other biotoxin illnesses have similar signs and symptoms. They are also treated similarly. Some of them are discussed on this site. This information is for educational purposes only. Nothing in this text is intended to serve as medical advice. All medical decisions should be made only with the guidance of your own personal medical authority. I am doing my best to get this data up quickly and correctly. If you find errors in this data, please let me know.

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Brief Explanation: Vascular Endothelial Growth Factor (VEGF) is a signal protein produced by cells that stimulates the growth of new blood vessels in response to low levels of oxygen. It also produces a profound increase in vascular permeability and edema. (Permeability describes the blood vessel walls ability to allow small molecules such as water, nutrients or even whole cells such as white blood cells to go in and out of the vessel.)

Too much VEGF or too little VEGF can create problems. Too much VEGF can lead to excess blood vessel growth and excess permeability of capillaries. Too little can lead to a lack of oxygen in the tissues and symptoms of Chronic Inflammatory Respons Syndrome (CIRS). Initially in CIRS it will be high but it becomes low over time.

Detailed Explanation: Vascular Endothelial Growth Factor (VEGF) is a sub-family of the platelet-derived growth factor family of cystine-knot growth factors. It is a signal protein produced as a response to capillary hypoperfusion and Hypoxia Inducible Factor (HIF). VEGF has been shown to be an endothelium-dependent vasodilator, exerting its effect through Nitric oxide and prostacyclin. Though there are four endogenous isoforms of VEGF. VEGF-A is the one most often discussed when someone mentions VEGF. VEGF induces vascular permeability, cell migration and protease production by endothelial cells, all of which are critical components of the angiogenic process, the main function attributed to VEGF.

Low oxygen levels stimulate angiogenesis (Angiogenesis is the term used for the formation of new blood vessels from pre-existing ones). Among the many angiogenic factors, VEGF is one of the most critical and specific factors that stimulate both physiological and pathological angiogenesis.VEGF's function is to create new blood vessels during embryonic development, after injury for wound healing, in muscle following exercise and new vessels to bypass blocked vessels. When blood circulation is inadequate, VEGF will usually increase to meet the demand. The increased VEGF brings new blood vessels into the area and there is greater delivery of oxygen to the area.

In addition to its ability to induce vessel growth, a growing body of evidence has shown that VEGF is a survival factor that can enhance cardiomyocytes and neuronal cell survival and reduce infarct size in the brain and heart. [6]

Too much VEGF can lead to increased angiogenesis and create rampant growth of blood vessels.VEGF is used by some tumors to grow and metastasize. Increased VEGF is also associated with excess microvascular hyperpermability during inflammation.

Too little VEGF leads to decreased angiogenesis and lack of oxygen to the tissues. This has been associated with heart and brain ischemia (lack of oxygen), neurodegeneration. In the brain, VEGF stimulates the growth of new blood vessels and works in other ways to keep brain cells healthy. VEGF is currently being studied to treat the debilitating and fatal disease of the central nervous system called spinocerebellar ataxia type 1 (SCA1). Low VEGF also leads to delayed wound healing, high blood pressure and many symptoms seen in CIRS.

In a healthy individual there is a balance between switching angiogenesis on and off. This balance can be reflected in certain lab markers such as VEGF. We want VEGF to stay in a normal level that is seen in healthy individuals.

A VEGF Signaling Pathway can be viewed here.

High VEGF:

Cancer: Solid cancers get to a certain size and quit growing without more VEGF. They need more VEGF to create more blood vessels to bring enough oxygen and nutrients into them as they grow. Cancers that make VEGF are able to grow bigger and to metastasize (travel to other places). VEGF inhibitors are used in the treatment of some cancers.

Wet Macular Degeneration: Too much VEGF can cause over growth of blood vessels in the retina causing wet macular degeneration. Drugs such as Ranibizumab are used to inhibit VEGF in the retina of the eye.

Low VEGF in CIRS (Biotoxin Illness)

Dr. Ritchie Shoemaker found in his research that his CIRS patients often had low VEGF leading to levels less than 31. This was induced by high cytokine levels. He found they needed to keep their VEGF in the range of 31-86.

People with biotoxin illness such as those who have CIRS due to water-damaged building, will generally have low VEGF if they are extremely sick. Initially, the VEGF will rise due to tissue hypoperfusion. It is activated by hypoxia inducible factor (HIF). TGF beta-1 will also be induced by HIF and as it rises,TGF beta-1 will lower the VEGF level. Folks with CIRS due to water-damaged building have high TGF beta-1 generally.

Research has shown that the mycotoxin called fumagillin from Aspergillus fumigatus inhibits multiple key angiogenic mediators. VEGF is one of them. This leads to tissue hypoxia which can be reversed by VEGF introduction. [1] Researchers have created a fumagillin analog named Lodamin which is one of the most potent and broad-spectrum antiangiogenesis inhibitors. It's action on VEGF (inhibits VEGF induced angiogenesis by 41%) and basic fibroblast growth factor (inhibits VEGF induced angiogenesis by 31%). [2]This shows just how potent a mycotoxin or mycotoxin analog can be in inhibiting angiogenesis.

What is happening in CIRS when there is low VEGF: Basically, you end up with decreased delivery of nutrients and oxygen via the capillaries.

Three is low capillary hypoperfusion so you have a reduced delivery of O2 which leads to a reduced mitochondrial function and a rise of lactate.

These people can not exercise. They will crash due to the lack of oxygen to the capillary beds. It appears they are not efficiently burning glucose. They turn to glycogen and soon run out of glycogen reserves. When their glycogen is used up it takes a couple days to build it back up again and this is why they get "post exertional fatigue" that lasts for a couple days. The capillary hypoperfusion and lack of oxygen can also lead to cognitive dysfunction and constant aching.

If they push themselves they will end up using fat reserves, but if they are leptin resistant, (Also due to the cytokine responses) they won't be able to burn the fatty acids directly. They will then turn to burning protein. These folks will say they are getting fat even though they are eating less and exercising as much as they can.

The person has a low VO2 max on pulmonary stress tests. Many have a VO2 of less than 20 if they are severely ill. The way to correct VO2 max in the CIRS patient is by raising their VEGF level to normal range. Using procrit and VIP can increase the VO2 to 40-50 in a couple weeks.

Raising VEGF in CIRS

First realize you would not want to raise VEGF if it is already high. You also would need to discuss this with an oncologist if you are treating a patient who has cancer and CIRS. High VEGF can promote some cancers.

Most research examines lowering VEGF as a treatment for abnormally high VEGF with certain types of cancers. There is an increasing body of research regarding raising VEGF to treat hypoxic brain and cardiovascular issues. There is less information on raising VEGF with nutrients or herbs. I actually suggest you work on lowering TGF beta-1 which will end up helping to lower VEGF. (You may note that many of the herbs and nutrients that lower TGF beta-1 are used to lower VEGF when it is high. Please realize that many of the nutrients and herbs do not act as drugs do. They often have amphoteric activity and may actually cause opposing things to happen in the body at different times.)

• High TGF beta-1 will lower VEGF, so one approach is to focus on lowering TGF beta-1 into normal limits. This should also raise the VEGF into normal limits.

Raising VEGF

Fish Oil: Omega 3 fatty acids 2.4 grams EPA and 1.8 grams DHEA per day. [14] Although there is research showing increased VEGF and angiogenesis in an ischemic condition with an enhanced fish oil diet, there is research showing it lowers VEGF and is antiangiogenic also. This is another situation where we see amphoteric activity.,

Low Amylose Diet as created by Dr. Ritchie Shoemaker.

Keeps insulin in control as insulin will increase inflammatory cytokines. Eat at least 6 ounces of protein each day and at least 3 servings of above ground vegetables and fruit every day. No simple sugars, maltodextrins, and corn syrup, no grains such as rice, wheat, rye, barley and oats, no bananas, no underground veggies except onions and garlic, – no nuts other than walnuts and almonds) can eat all fruit except bananas, all above ground veggies and meat.

Scutellaria baicalensis root and Baicalin: Scutellaria baicalensis root and it's constituent called baicalin have been found to raise VEGF expression through the activation of the ERRα pathway. In vitro work, but looks good. Especially interesting when you take into account this herb is used for strokes traditionally. [3]

Although baicalin can induce angiogenesis by stimulating VEGF expression,[6] it has been previously shown to inhibit angiogenesis by suppressing endothelial cell proliferation, migration, and tube formation in vitro, as well as vessel formation in chicken chorioallantoic membrane.[7] This study was focused on the effect of baicalin on endothelial cells, whereas the VEGF study was focused on the effect of baicalin on VEGF expression, a different aspect in regulating angiogenesis. It is possible that baicalin has both pro-angiogenesis (via elevating VEGF expression as shown in [6] study) and anti-angiogenesis (via suppressing endothelial cell function as shown in the [7] study) activities.

Resveratrol shows increased VEGF levels in vitro and in vivo (rats). At low dosage (2 ng/mL), resveratrol induces angiogenic actions, whereas at higher dosages (1.2 mg/L), it can inhibit cell survival and angiogenic pathways. Furthermore, pharmacokinetics, bioavailability and metabolism likely play a critical role in appropriate delivery strategies to produce appropriate therapeutic outcomes. Specifically, oral administration leads to rapid absorption to plasma, liver, kidney and heart.

Astragalus has been shown to promote angiogenesis and induces VEGF expression. [4],[5]

Curcumin (From tumeric) Several studies have highlighted the pro-angiogenic properties of curcumin by both oral and topical application. Specifically, serum-free curcumin application showed significant up-regulation of VEGF. Additionally, Kiran and colleagues showed significant capillary network formation in HUVEC and RAEC cultures, vessel sprouting in aortic ring assays, and increased vascular density in CAM assays in response to curcumin treatment. Supplementation of curcumin along with serum caused down-regulation of VEGF. So this suggests a different response depending on extracellular microenvironment.[13] I would add here that Curcumin decreases TGF beta-1 and when you lower TGF beta-1, you raise VEGF.

Erythropoetin has been shown in various research to elevate VEGF and Dr. Shoemaker has used Procrit to raise VEGF. Additionally, patients who go to high altitudes will also find it raises their low VEGF levels.

Vasoactive Intestinal Polypeptide(VIP): Has also been shown to raise VEGF in research by Dr. Ritchie Shoemaker.

Catechins such as EGCG have been reported to both inhibit and stimulate VEGF expression. [8], [9]

Quercetin has been shown to induce VEGF expression through increasing HIF-1α expression. [10]

47 crude plant extracts were tested in a CAM assay and in vitro bovine aortic endothelial cell (BAEC) proliferation assays. Of these, 24 demonstrated angiogenic properties with Epimedium sagittatum, Trichosanthes kirilowii and Dalbergia odorifera performing the strongest in both CAM and BAEC models. These may be acting as stimulants to VEGF.[11]

A few more scientific details on VEGF

VEGF expression is induced by growth factors, oncogenes, and hypoxia. The key regulator of VEGF expression in response to hypoxia is hypoxia-inducible factor-1. Levels of HIF-1α expression are determined by the rates of protein synthesis (regulated via an oxygen-independent mechanism) and protein degradation (regulated via an oxygen-dependent mechanism). HIF-1 activates VEGF transcription by binding to the hypoxia response element (HRE) in the VEGF promoter. In addition to HRE, multiple transcription factor-binding sites, including ERR, AP-1, Sp-1, Stat3, and CREB, have been identified within the VEGF promoter.[3]

Recent studies have found that peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a potent ligand-independent coactivator that interacts with ERRα and also a major regulator of mitochondrial function in response to exercise and other stimuli. Through the activation of ERR-α, PGC-1α has been shown to powerfully induce VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo, as well as in breast cancer cells, in an HIF-1α independent pathway.[3]

1. Future Microbiol. 2013 Nov;8(11):1453-62. doi: 10.2217/fmb.13.114.
Angiogenesis at the mold-host interface: a potential key to understanding and treating invasive aspergillosis. PMID: 24199803 [PubMed]
Ben-Ami R.

2. Nat Biotechnol. 2008 Jul;26(7):799-807. doi: 10.1038/nbt1415. Epub 2008 Jun 29.
An orally delivered small-molecule formulation with antiangiogenic and anticancer activity.
Benny O1, Fainaru O, Adini A, Cassiola F, Bazinet L, Adini I, Pravda E, Nahmias Y, Koirala S, Corfas G, D'Amato RJ, Folkman J. PMID: 18587385 [PubMed]

Entire free article is here!

3. Cardiovasc Res. Feb 1, 2011; 89(2): 426–435.
Published online Sep 16, 2010. doi: 10.1093/cvr/cvq296
PMCID: PMC3020130
Baicalin increases VEGF expression and angiogenesis by activating the ERRα/PGC-1α pathway
Keqiang Zhang,1,2 Jianming Lu,1 Taisuke Mori,3 Leslie Smith-Powell,2 Timothy W. Synold,2 Shiuan Chen,3 and Wei Wen1,*

Entire free article is here!

4. Han DO, Lee HJ, Hahm DH. Wound-healing activity of Astragali Radix in rats. Methods Find Exp Clin Pharmacol. 2009;31:95–100. PMID: 19455264

5.Hikino H, Funayama S, Endo K. Hypotensive principle of Astragalus and Hedysarum roots. Planta Med. 1976;30:297–302. [PubMed]

6. Bioessays. 2004 Sep;26(9):943-54.VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.Storkebaum E1, Lambrechts D, Carmeliet P. [PubMed]

7. Int J Cancer. 2003 Sep 10;106(4):559-65. Baicalein and baicalin are potent inhibitors of angiogenesis: Inhibition of endothelial cell proliferation, migration and differentiation.
Liu JJ1, Huang TS, Cheng WF, Lu FJ. [PubMed]

8. Zhou YD, Kim YP, Li XC, Baerson SR, Agarwal AK, Hodges TW, et al. Hypoxia-inducible factor-1 activation by (-)-epicatechin gallate: potential adverse effects of cancer chemoprevention with high-dose green tea extracts. J Nat Prod. 2004;67:2063–2069. [PMC free article]

9. Sartippour MR, Shao Z-M, Heber D, Beatty P, Zhang L, Liu C, et al. Green tea inhibits vascular endothelial growth factor (VEGF) induction in human breast cancer cells. J Nutr. 2002;132:2307–2311. [PubMed]

10. Mol Pharmacol. 2007 Jun;71(6):1676-84. Epub 2007 Mar 21.chro
Quercetin activates an angiogenic pathway, hypoxia inducible factor (HIF)-1-vascular endothelial growth factor, by inhibiting HIF-prolyl hydroxylase: a structural analysis of quercetin for inhibiting HIF-prolyl hydroxylase.
Jeon H1, Kim H, Choi D, Kim D, Park SY, Kim YJ, Kim YM, Jung Y. [PubMed]

11. Life Sci. 2004 Apr 2;74(20):2467-78.
Angiogenesis and anti-angiogenesis activity of Chinese medicinal herbal extracts.
Wang S1, Zheng Z, Weng Y, Yu Y, Zhang D, Fan W, Dai R, Hu Z.[PubMed]

12. Organogenesis. 2008 Oct-Dec; 4(4): 215–227.
Engineering vascularized tissues using natural and synthetic small molecules
Lauren S Sefcik,1 Caren E Petrie Aronin,1 and Edward A Botchweycorresponding author1–3 [PubMed]

13. J Cell Physiol. 2008 Apr;215(1):251-64.
Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response. Kiran MS1, Kumar VB, Viji RI, Sherin GT, Rajasekharan KN, Sudhakaran PR. [PubMed]

14. Atherosclerosis. 2013 Aug;229(2):295-303.
Fish oil-enriched diet protects against ischemia by improving angiogenesis, endothelial progenitor cell function and postnatal neovascularization.
Turgeon J1, Dussault S, Maingrette F, Groleau J, Haddad P, Perez G, Rivard A. PMID: 23880179 [PubMed]

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