What Is VEGF and Its Role in Health and Disease?

Vascular endothelial growth factor, or VEGF, is a signaling protein that tells the body to build new blood vessels and maintain existing ones. It earned its name because it acts primarily on the endothelial cells lining the inside of blood vessels, but research over the past few decades has revealed a much broader reach: VEGF influences wound healing, kidney filtration, nerve cell survival, reproduction, and inflammation. That same versatility makes it a central player in diseases ranging from cancer to blindness, and drugs that block or harness VEGF have become some of the most widely used treatments in oncology and ophthalmology.

The VEGF Family and Its Receptors

VEGF is not a single molecule but a family of related proteins. The most studied member, VEGF-A, is the one people usually mean when they say “VEGF.” Its gene can be read in several different ways by the cell, producing at least four distinct protein versions (isoforms). The shortest version, VEGF121, floats freely through tissue fluid. Longer versions like VEGF189 and VEGF206 stick tightly to the surrounding tissue scaffold, while VEGF165 sits in the middle, partly free and partly bound.¹ This mix matters because it creates both local and distant signaling: some VEGF stays right where it was made, while some diffuses further away to recruit blood vessels from a distance.

Other family members include VEGF-B, VEGF-C, and VEGF-D. VEGF-C and VEGF-D primarily drive the growth of lymphatic vessels rather than blood vessels, acting through a receptor called VEGFR-3 that is concentrated on lymphatic cells.² VEGF-B has drawn interest for its neuroprotective properties, which we will get to later.

The isoforms do not all hit the same targets equally hard. VEGF-A165 binds one of the main receptors, VEGFR-1, roughly a thousand times more tightly than the shorter VEGF-A121 does. And the different splice variants show strikingly different preferences between VEGFR-1 and VEGFR-2, the two receptors that matter most for blood vessel biology.³ Those receptor preferences shape whether the downstream outcome is more about vessel growth, vessel permeability, or cell migration.

How VEGF Signals Inside Cells

When VEGF lands on the outside of an endothelial cell, it causes two receptor molecules to pair up and switch on their internal signaling machinery. That activation sets off a cascade of events inside the cell: instructions to divide, to migrate toward the VEGF source, and to form tube-like structures that become new capillaries. Interestingly, much of this signaling does not happen at the cell surface. After the receptor-VEGF pair is pulled inside the cell in small membrane bubbles, key steps continue from these internal compartments, and the timing and location of that internal trafficking help determine the outcome.⁴

The two main receptors divide labor. VEGFR-1 guides cell migration by reorganizing the cell’s internal skeleton, while VEGFR-2 (also called KDR) influences migration differently, by changing how cells grip onto surrounding tissue.⁵ This split means the cell can fine-tune its response depending on which receptor is engaged.

What Turns VEGF On

Low oxygen is the most powerful trigger. When tissue does not get enough blood supply, cells ramp up VEGF production dramatically. Researchers identified a short stretch of DNA in the VEGF gene’s control region that acts as an oxygen-sensing switch: when oxygen drops, a protein called hypoxia-inducible factor (HIF-1) binds to this enhancer and cranks up VEGF production.⁶ This makes intuitive sense: tissue that is starved of oxygen sends out a molecular distress signal to recruit new blood vessels. But the same mechanism becomes a liability when tumors exploit it to build their own blood supply.

Other triggers include inflammatory signals, certain hormones, and mechanical forces like the shear stress of blood flow. In the uterus, for instance, estrogen and progesterone boost VEGF production during the menstrual cycle. During the mid-secretory phase, when the uterine lining is preparing for a possible embryo, VEGF staining becomes intense in both the glands and the surrounding tissue. It stays high in early pregnancy, where it helps maintain the blood supply the developing placenta needs.⁷

Wound Healing

VEGF is one of the strongest pro-angiogenic signals in the skin, and the amount present in a wound meaningfully influences how well it heals.⁸ A fresh wound needs new capillaries to deliver oxygen and nutrients to the repair zone, and VEGF levels spike during the early days of healing when capillary growth is at its peak. Beyond stimulating blood vessel formation, experimental data suggests VEGF also encourages collagen deposition and the regrowth of the surface skin layer.⁹

Animal studies have explored combining VEGF with other molecules to accelerate healing. In one experiment, topical application of VEGF together with a glycosaminoglycan called mesoglycan closed skin wounds in mice faster than either substance alone, producing well-organized tissue with a significant number of new blood vessels.¹⁰ Results like these keep VEGF on the radar for future wound-care products, although translating mouse results to human therapies is always a long road.

Roles Outside Blood Vessels

VEGF’s influence extends well beyond building new capillaries. In the kidneys, cells called podocytes produce VEGF that acts on the neighboring blood vessel cells of the filtering unit (the glomerulus). Deleting VEGF from podocytes in animal models causes serious damage to the filtration barrier, confirming that a steady, local supply of VEGF is essential for normal kidney function.¹¹ The protein also helps maintain the tiny pores in kidney blood vessels that allow the high-speed filtration your kidneys perform every day.¹²

In the nervous system, VEGF supports nerve cell survival, new nerve cell generation, and the migration and guidance of growing nerve fibers.¹³ Laboratory studies have shown that VEGF acts as a direct survival factor for motor neurons, and animals engineered to produce abnormally low levels of VEGF develop motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS).¹⁴ VEGF-B, a family member with a notably clean safety profile in preclinical work, has protected motor neurons in ALS animal models and is being watched as a potential therapeutic candidate.

In the lymphatic system, VEGF-C and VEGF-D work through VEGFR-3 to promote the growth and maintenance of lymphatic vessels. VEGFR-3 plays a critical early role in remodeling embryonic blood vessels, then shifts to a lymphatic focus later in development.² Control over how VEGF-C and VEGF-D are processed and made available adds another layer of regulation, ensuring lymphatic vessels grow only when and where they are needed.¹⁵

VEGF in Cancer

Tumors cannot grow beyond a few millimeters without a blood supply, so they co-opt the body’s own VEGF machinery to build one. In colorectal cancer, for example, researchers have tracked how different VEGF family members switch on at different stages: VEGF-A and VEGF-B appear early, during the benign adenoma stage, while VEGF-C ramps up in advanced disease, when the tumor is more likely to spread to distant sites through the lymphatic system.¹⁶ This staged activation helps explain why anti-VEGF drugs are sometimes effective at slowing progression but rarely cure a cancer on their own.

Bevacizumab, the most widely used anti-VEGF cancer drug, works primarily by starving tumors of their blood supply. But there is evidence it also has direct effects on tumor cells. Precise cell-counting experiments have shown that bevacizumab can inhibit tumor cell growth by roughly 40–47%, an effect that standard metabolic assays miss because the drug simultaneously boosts mitochondrial activity in those cells, masking the growth inhibition.¹⁷

A persistent challenge is resistance. Tumors eventually find workarounds, activating alternative blood-vessel-building pathways or recruiting supportive cells from the surrounding tissue that supply growth factors the anti-VEGF drug cannot block.¹⁸ These resistance mechanisms are broadly grouped into VEGF-dependent changes (mutations that reduce drug binding) and VEGF-independent routes (entirely separate signaling pathways that take over the job).¹⁹

Eye Disease and Anti-VEGF Injections

One of the most successful applications of anti-VEGF medicine is in ophthalmology. In diabetic retinopathy, excess VEGF drives abnormal blood vessel growth in the retina and fluid leakage that causes swelling, leading to complications like diabetic macular edema and proliferative retinopathy.²⁰ In wet age-related macular degeneration, a similar process of abnormal vessel growth beneath the retina threatens central vision.

Anti-VEGF drugs injected directly into the eye, including ranibizumab, bevacizumab, and aflibercept, have transformed outcomes for both conditions. A systematic review and meta-analysis found that ranibizumab and aflibercept performed similarly in visual acuity improvement and lesion-size reduction in wet macular degeneration, while bevacizumab showed a small but statistically significant difference compared to ranibizumab.²¹ A separate meta-analysis comparing dosing schedules found that treat-and-extend regimens delivered similar visual outcomes to monthly injections but with roughly four and a half fewer injections over the study period, and fewer clinic visits than an as-needed approach.²² For patients who dread monthly eye injections, that flexibility is a meaningful quality-of-life improvement.

Cardiovascular Side Effects of Anti-VEGF Drugs

Because VEGF is essential for normal blood vessel maintenance throughout the body, blocking it can cause problems beyond the intended target. Hypertension is the most common cardiovascular side effect of VEGF inhibitor cancer drugs, and it can become severe enough to require dose reduction or drug withdrawal, compromising the anti-cancer benefit.²³ This is a real trade-off in oncology: better cancer control at the cost of increased cardiovascular risk. Clinicians have to monitor blood pressure closely and sometimes switch agents or add blood-pressure medications to keep patients safely on treatment.

The Disappointing History of VEGF Gene Therapy for the Heart

If blocking VEGF can treat cancer and eye disease, the obvious flip side is whether delivering extra VEGF could rescue heart tissue starved of blood flow after coronary artery disease narrows the vessels. Early clinical trials were encouraging, reporting large increases in exercise tolerance and marked reductions in angina symptoms, along with some evidence of improved blood flow and heart function.²⁴

But rigorously controlled studies told a different story. The NORTHERN trial, a double-blind placebo-controlled study that injected VEGF165 gene therapy directly into the heart muscle using a catheter guidance system, found no benefit over placebo for any endpoint: not blood flow measured by imaging, not exercise time, and not angina symptoms. Both groups improved, suggesting a strong placebo response, but the VEGF-treated patients did no better.²⁵ Preclinical results for cardiovascular VEGF therapy continue to look promising, but translating them into proven human treatments remains an unsolved problem.²⁶

VEGF in Rheumatoid Arthritis

Joint inflammation in rheumatoid arthritis involves a thickened, overgrown lining tissue called the synovium. Keeping that mass of inflammatory cells alive requires oxygen and nutrients, so new blood vessel growth becomes part of the disease process itself. VEGF is upregulated in RA joints by both inflammatory signals and the low-oxygen environment within the swollen synovium. Blood levels of VEGF track with disease activity in RA patients, making it a useful marker of how active the joint inflammation is.²⁷ Beyond feeding the inflamed tissue, VEGF also acts directly as an inflammatory molecule in RA and protects the overgrown synovial cells from dying, which compounds the joint damage.²⁸

POEMS Syndrome and VEGF as a Biomarker

One of the most striking clinical uses of VEGF measurement is in a rare condition called POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes). Patients with POEMS have dramatically elevated VEGF levels in their blood, and how fast those levels fall after treatment turns out to be one of the best predictors of outcome. Patients whose serum VEGF dropped to normal within six months of treatment had far longer relapse-free survival compared to those whose levels stayed high.²⁹ A follow-up study confirmed that patients with a complete VEGF response had a three-year relapse-free survival of about 94%, compared to roughly 57% for partial responders and 0% for non-responders.³⁰ Regular VEGF monitoring has become standard in managing POEMS, although its sensitivity for predicting relapse after remission is moderate rather than perfect.

Exercise and VEGF

Physical exercise is one of the most reliable natural ways to boost VEGF in skeletal muscle. When you work out, the temporarily oxygen-hungry muscle fibers ramp up VEGF production, which triggers the growth of new capillaries to serve those muscles. In one study, a single bout of exercise in untrained muscle raised VEGF messenger RNA levels about 17-fold. But here is the catch: as the muscle adapted to regular training, the VEGF spike after each session shrank, suggesting a negative feedback loop once the capillary network has expanded enough to meet demand.³¹

This exercise-VEGF connection is not limited to healthy people. In heart failure patients, an exercise training program doubled VEGF protein levels in skeletal muscle and increased peripheral exercise capacity by about 36%.³² The finding helps explain why exercise training improves function in heart failure: it is not just about the heart getting stronger, but about the muscles building a better blood supply to use oxygen more efficiently.

Viruses That Carry Their Own VEGF

Evolution has handed at least one virus family its own version of VEGF. Orf virus, a parapoxvirus that primarily infects sheep and goats but can jump to humans, encodes a protein with homology to mammalian VEGF.³³ The skin lesions this virus causes are characterized by massive capillary proliferation and dilation in the dermis, and the viral VEGF is directly responsible. When researchers knocked out the VEGF gene from the virus, the recombinant virus lost the ability to stimulate blood vessel growth, endothelial cell division, and vascular permeability at the site of infection.³⁴

Different parapoxvirus strains produce viral VEGFs that vary widely in amino acid sequence and in which mammalian receptors they activate, yet all of them stimulate endothelial cell proliferation.³⁵ The virus benefits from this blood vessel growth because a richer local blood supply likely delivers more immune cells and nutrients that the virus exploits for replication. It is a vivid example of how a host signaling molecule can be hijacked for an entirely different purpose.

Controlled-Release Delivery for Regenerative Medicine

One of the practical hurdles with therapeutic VEGF is that it disappears quickly from tissue. Inject it as a liquid and it gets broken down or washed away within hours, before it can do much good. Researchers have been developing slow-release delivery systems to solve this. Collagen-based hydrogels, for instance, can be loaded with VEGF and implanted under the skin, releasing the growth factor gradually as the gel biodegrades. In mouse experiments, these gels produced significant new blood vessel growth around the implant, far more than free VEGF in solution, and the duration of the effect tracked with how slowly the gel broke down.³⁶

Heparin-functionalized hydrogels made from gelatin or albumin offer another approach, with tunable release rates depending on the base material. Albumin-based versions released more cumulative VEGF over 21 days than gelatin-based versions, likely because of differences in protein charge and degradation behavior.³⁷ For the lymphatic side of things, alginate hydrogels loaded with VEGF-C or VEGF-D promoted lymphatic endothelial cell sprouting in culture at rates comparable to or slightly better than simply adding the growth factors to the cell medium, while offering the advantage of sustained delivery.³⁸ These delivery platforms are still largely at the laboratory stage, but they represent the kind of engineering that will eventually be needed to make VEGF-based therapies practical for wound repair, lymphedema, and ischemic tissue rescue.