Are There Risks or Side Effects Associated With Treatments That Increase Vascular Endothelial Growth Factor (VEGF)?

Understanding Why VEGF Is Increased in the First Place

Vascular Endothelial Growth Factor, commonly known as VEGF, is a naturally occurring protein in the human body that stimulates the growth of new blood vessels. This biological process is called angiogenesis. Angiogenesis is essential during wound healing, after injury, and in restoring blood flow to tissues that are not receiving enough oxygen. Because of this role, researchers have explored treatments that increase VEGF levels to help conditions such as peripheral artery disease, heart disease, wound healing problems, and even hair loss. However, increasing VEGF is not a neutral intervention. Blood vessel growth is powerful, and when it is stimulated artificially, unintended effects may occur.

The central question is whether increasing VEGF can produce risks or side effects. Research conducted over the past two decades shows that while the idea is promising, there are documented concerns involving abnormal vessel growth, swelling, inflammation, possible tumor progression, and inconsistent clinical benefits. The evidence comes from clinical trials in humans, animal experiments, and long-term biological studies.

What Clinical Trials Reveal About Safety Concerns

One of the most important large-scale studies evaluating VEGF-based therapy was the TAMARIS trial published in 2011 in The New England Journal of Medicine. This Phase 3 randomized, double-blind, placebo-controlled study was conducted by Belch and colleagues in 2011. The trial included 525 patients with critical limb ischemia, a severe form of peripheral artery disease in which blood flow to the legs is dangerously reduced. Participants were randomly assigned to receive intramuscular injections of a plasmid containing the gene for fibroblast growth factor (which works through angiogenic pathways related to VEGF signaling) or placebo. Patients were followed for 12 months. The primary outcome was amputation-free survival, meaning survival without losing the affected limb. Results were evaluated using clinical examinations, imaging studies, and statistical survival analysis.

The study found no significant improvement in amputation-free survival in the treatment group compared with placebo. Regarding safety, overall adverse events were similar between groups, but concerns were raised about theoretical risks such as abnormal vascular growth and cancer stimulation. A limitation of this study was that although it was large and rigorously designed, it evaluated a specific gene therapy approach rather than all VEGF-increasing therapies. Therefore, its conclusions cannot automatically be generalized to every VEGF-related intervention.

Earlier, in 2003, Rajagopalan and colleagues conducted the RAVE trial (Randomized Angiogenesis with VEGF) published in Circulation. This randomized, double-blind trial involved 105 patients with intermittent claudication, a condition causing leg pain during walking due to poor circulation. Participants received intramuscular injections of VEGF121 gene therapy or placebo and were followed for 6 months. The primary method of evaluation was treadmill exercise testing to measure walking time, along with imaging studies to assess blood flow. The study found no significant improvement in exercise performance compared with placebo. Peripheral edema, which is swelling caused by fluid accumulation in tissues, occurred more frequently in the VEGF-treated group. The duration of the study was relatively short, and the sample size was modest, limiting the ability to detect rare long-term side effects.

Peripheral edema occurs because VEGF increases vascular permeability. Vascular permeability refers to how easily fluid passes through blood vessel walls. When permeability increases, fluid can leak into surrounding tissues, causing swelling. This biological mechanism explains why fluid retention is one of the most consistently observed side effects in VEGF-stimulating therapies.

Could Increasing VEGF Promote Cancer Growth?

One of the most discussed theoretical risks of increasing VEGF is cancer progression. Tumors require blood vessels to grow beyond a small size. VEGF is one of the primary signals tumors use to recruit new blood vessels. In fact, several approved cancer drugs work by blocking VEGF to prevent tumor angiogenesis. Research by Ferrara in 2004, published in Nature Reviews Cancer, explained how VEGF drives tumor vascularization and supports malignant growth. The conclusions were based on animal models and molecular biology studies examining VEGF signaling pathways in cancer cells and endothelial cells, which are the cells lining blood vessels.

Although clinical trials of VEGF gene therapy have not conclusively demonstrated increased cancer incidence during their follow-up periods, most trials were not long enough to evaluate long-term cancer risk. Many lasted between 6 and 12 months. Cancer development can take years. Therefore, the absence of evidence is not necessarily evidence of absence. This limitation is acknowledged in multiple NIH-supported angiogenesis studies.

The concern remains theoretical but biologically plausible. A biologically plausible risk means that based on how the body works, the risk makes sense scientifically, even if it has not yet been definitively proven in large long-term human studies.

Eye and Vascular Complications: Lessons From Opposite Approaches

Interestingly, much of what is known about VEGF risks comes from the opposite approach: blocking VEGF in diseases like diabetic retinopathy and age-related macular degeneration. The U.S. Food and Drug Administration has approved several anti-VEGF drugs because excessive VEGF contributes to abnormal and fragile blood vessel growth in the eye. Studies funded by the National Eye Institute, part of the NIH, have shown that too much VEGF causes leaking, fragile vessels that damage vision.

This body of research demonstrates that VEGF is tightly regulated in healthy individuals. Both too little and too much can be harmful. When VEGF levels rise excessively, blood vessels may grow in disorganized ways. Disorganized angiogenesis can result in fragile vessels prone to leakage or bleeding. Although therapeutic VEGF stimulation aims to be controlled, predicting precise biological responses remains challenging.

Inflammation and Abnormal Vessel Formation

Animal studies have also explored the effects of sustained VEGF overexpression. For example, research published in the early 2000s in peer-reviewed journals indexed in PubMed examined transgenic mice engineered to overproduce VEGF in specific tissues. These studies typically lasted several weeks to months and evaluated tissue samples under a microscope to measure vessel density and structure. Findings showed that chronic VEGF overexpression sometimes led to abnormal, enlarged, and leaky vessels. Evaluation methods included histological analysis, which means microscopic examination of stained tissue sections, and measurement of inflammatory markers in blood samples.

A criticism of animal studies is that results in mice do not always translate directly to humans. However, they provide insight into biological mechanisms and potential safety signals.

What About Hair Growth and Community Discussions?

In the context of hair loss, VEGF has attracted attention because hair follicles require blood supply to grow. Some experimental treatments and discussions in online communities suggest that increasing scalp blood flow or stimulating VEGF might improve hair growth. Scientific studies have shown that minoxidil, an FDA-approved hair loss treatment, increases VEGF expression in dermal papilla cells. Research published in the Journal of Investigative Dermatology in 2004 examined human dermal papilla cells in laboratory conditions and found that minoxidil upregulated VEGF production. The method involved cell culture experiments, molecular assays measuring messenger RNA levels, and protein quantification. These were laboratory-based experiments rather than long-term safety trials in humans.

Community discussions on platforms such as Tressless frequently mention VEGF in the context of microneedling, topical treatments, or experimental compounds. Users often report increased shedding, scalp redness, or temporary swelling. These are anecdotal reports, meaning they are based on personal experience rather than controlled trials. Anecdotal evidence cannot establish cause and effect, but it highlights real-world concerns. The major limitation is that these experiences are not verified through controlled scientific methodology and are subject to placebo effects, reporting bias, and inconsistent dosing practices.

So, Are There Real Risks?

The scientific answer is that treatments designed to increase VEGF can carry risks, particularly related to fluid leakage, swelling, abnormal blood vessel growth, and theoretical cancer promotion. Large human trials have not demonstrated dramatic increases in severe adverse events over short follow-up periods, but they have also failed to show consistent long-term benefit in many cardiovascular applications. Short study durations, modest sample sizes, and variability in gene delivery methods limit the strength of safety conclusions.

VEGF is not inherently dangerous. It is essential for life. However, artificially elevating it beyond natural regulatory control introduces biological uncertainty. Medicine has learned from decades of angiogenesis research that blood vessel growth must be balanced carefully. Excess stimulation can create fragile, leaky, or disorganized vessels. Insufficient stimulation impairs healing.

The evidence therefore suggests cautious optimism at best. VEGF-stimulating therapies remain under investigation, and long-term safety data are still limited. Individuals considering treatments that claim to increase VEGF should consult qualified medical professionals and rely on therapies that have undergone rigorous regulatory review.

User Experiences

Public discussions within the Tressless community reflect a mixture of curiosity and caution. Many users express hope that increasing blood flow or stimulating angiogenesis could improve hair density. Others report side effects such as scalp irritation, temporary swelling, or increased shedding phases. Some users also voice concern about theoretical cancer risks, often referencing scientific articles about VEGF and tumor angiogenesis.

These conversations reveal a gap between experimental science and consumer-level application. While laboratory data show that VEGF can support hair follicle activity, long-term controlled human trials specifically evaluating VEGF-targeted hair treatments are limited. Community experiences are valuable for understanding perceived outcomes, but they cannot replace randomized controlled trials.

Ultimately, based on current research, there are potential risks and side effects associated with treatments that increase VEGF. The degree of risk depends on dosage, delivery method, patient characteristics, and duration of exposure. Continued research, especially long-term human trials, is essential before such treatments can be considered fully safe.

References

Belch, J., Hiatt, W. R., Baumgartner, I., Driver, I. V., Nikol, S., Norgren, L., Van Belle, E., et al. (2011). Effect of fibroblast growth factor NV1FGF on amputation and death: A randomized placebo-controlled trial of gene therapy in critical limb ischemia (TAMARIS). The New England Journal of Medicine, 365(17), 1601–1612. https://www.nejm.org/doi/full/10.1056/NEJMoa1104666

Rajagopalan, S., Mohler, E. R., Lederman, R. J., Mendelsohn, F. O., Saucedo, J. F., Goldman, C. K., Blebea, J., et al. (2003). Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: A randomized, double-blind, placebo-controlled study (RAVE). Circulation, 108(16), 1933–1938. https://pubmed.ncbi.nlm.nih.gov/14568903/

Ferrara, N. (2004). Vascular endothelial growth factor: Basic science and clinical progress. Nature Reviews Cancer, 4(8), 617–625. https://pubmed.ncbi.nlm.nih.gov/15286740/

Lachgar, S., Charveron, M., Gall, Y., & Bonafe, J. L. (1998/2004 related mechanistic studies). Minoxidil upregulates VEGF in dermal papilla cells. Journal of Investigative Dermatology. https://pubmed.ncbi.nlm.nih.gov/15086512/