Angiogenesis: Definition, How New Blood Vessels Form, VEGF, Role in Disease, Therapies and Fat Grafting

What is angiogenesis?

Angiogenesis is the formation of new blood vessels. The process involves endothelial cells, which line the inside of vessels. They migrate, grow and change into new vessels under the control of chemical signals such as vascular endothelial growth factor (VEGF) [1]. A physiology text published by NCBI Bookshelf defines it as the growth of blood vessels from the existing vasculature. The text notes that it happens throughout life, from before birth into old age [2]. The National Cancer Institute (NCI) likewise describes angiogenesis simply as blood vessel formation [1].

The process matters because tissues rely on nearby capillaries to exchange nutrients and waste. No metabolically active tissue in the body is more than a few hundred micrometers from a capillary [2]. When tissue grows, heals or is short of oxygen, angiogenesis is how its blood supply grows to match.

Angiogenesis vs vasculogenesis

The two terms are often confused. Vasculogenesis is how the embryo first builds blood vessels from scratch, using precursor cells called angioblasts that come from mesodermal stem cells. Angiogenesis builds on vessels that already exist [2].

Feature	Angiogenesis	Vasculogenesis
Starting point	Existing blood vessels	Angioblasts (vessel precursor cells) formed from mesodermal stem cells
Main timing	Throughout life, before birth to old age	Initial vessel formation in the embryo
Main cell type	Endothelial cells of existing vessels	Differentiating precursor cells
Source	[2]	[2]

How new blood vessels form: sprouting and intussusceptive angiogenesis

Sprouting angiogenesis

In the best-described form, a new capillary grows out like a sprout from an existing vessel. The textbook describes this sequence of steps [2]:

The basement membrane around the parent vessel is broken down.
Endothelial cells multiply.
The cells migrate toward the signal that is attracting them.
They form a tube with an open channel (lumen).
Neighbouring sprouts join to form loops, and blood begins to flow.
Surplus branches are removed (pruning).
Pericytes, the support cells around capillaries, attach and stabilize the new vessel.

Intussusceptive (splitting) angiogenesis

In a second form, an existing vessel splits in two when pillars of tissue form across its channel. According to the same source, this splitting route is more efficient than sprouting where capillaries are already present [2].

VEGF and the regulation of angiogenesis

Angiogenesis depends on a balance of chemical signals that switch it on and off. VEGF-A is the main signal that switches it on. Cells that are short of oxygen (hypoxic) release VEGF-A, which draws new vessels toward the tissue that needs them. The protein is so important in development that losing half of it is fatal to the embryo because the vessels do not form properly [2]. Most approved drugs that block angiogenesis act on VEGF or its receptors [1][3].

Angiogenesis in health

Angiogenesis is part of normal physiology [2]:

Growth and development: it starts before birth and continues throughout life.
Exercise: physical training causes new capillaries to grow in skeletal muscle.
Adipose (fat) tissue: the network of blood vessels in fat tissue changes as body weight goes up or down.
Wound healing: new vessels supply tissue that is being repaired.

Angiogenesis in disease

Tumor angiogenesis

Solid tumors need a blood supply to grow larger than a few millimeters. They trigger angiogenesis by releasing chemical signals or by prompting nearby normal cells to release them. The new vessels bring oxygen and nutrients. That lets the tumor grow, invade nearby tissue and spread (metastasize) [1]. The idea of targeting this process goes back to Judah Folkman's 1971 paper in the New England Journal of Medicine. According to a 2010 editorial in the Journal of Oncology, Folkman proposed four ideas [4]:

Solid tumors cannot grow beyond about 2–3 mm³ without forming new vessels.
Tumor cells stimulate vessel growth from surrounding vessels.
Blocking angiogenesis could hold tumors in a dormant state.
Long-term antiangiogenic treatment could be given safely.

The same editorial notes that in practice, tumors often became resistant to antiangiogenic drugs [4].

Eye disease

In wet age-related macular degeneration (AMD), VEGF makes abnormal blood vessels grow in the wrong place at the back of the eye. These vessels bleed and leak. Anti-VEGF injections are the most common treatment used to slow vision loss from wet AMD. Patients usually start with monthly injections, and the doctor then decides how often further injections are needed [5].

Angiogenesis inhibitors in medicine

Angiogenesis inhibitors are drugs that disrupt the signals that drive new vessel growth. In a fact sheet last reviewed in 2018, NCI listed these as FDA-approved cancer drugs with antiangiogenic activity: axitinib, bevacizumab, cabozantinib, everolimus, lenalidomide, lenvatinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, vandetanib and ziv-aflibercept [1]. Bevacizumab is a humanized monoclonal antibody (a lab-made antibody adapted to the human immune system) that binds VEGF-A [3]. It is used in several cancers [3]:

metastatic colorectal cancer
non-squamous non-small cell lung cancer
glioblastoma
metastatic renal cell carcinoma
cervical cancer
hepatocellular carcinoma
ovarian, fallopian tube and primary peritoneal cancer

Area	Aim	Examples	Status
Cancer	Block tumor vessel growth	Bevacizumab, VEGF-receptor kinase inhibitors	FDA-approved for specified cancers [1][3]
Wet AMD	Stop abnormal, leaking eye vessels	Anti-VEGF injections into the eye	Most common treatment [5]
Peripheral artery disease	Stimulate new vessels in limbs with poor blood flow	VEGF, FGF or HGF gene or protein therapy	Randomized trials largely negative on primary endpoints [6]

Safety. NCI lists these common side effects of angiogenesis inhibitors [1]:

bleeding
clots in the arteries
high blood pressure
slow wound healing
protein in the urine

Rare but serious problems include tears in the gut wall (gastrointestinal perforation) and fistulas [1]. For bevacizumab, reported rates of high blood pressure range from 19% to 42% [3]. These drugs are prescribed and monitored by specialists.

Therapeutic angiogenesis: trying to grow new vessels

The opposite approach is to stimulate angiogenesis where blood flow is poor, such as in peripheral artery disease (PAD). A 2017 review in JACC: Basic to Translational Science summarized trials of three growth factors: VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Most did not meet their main goals, even though animal studies had looked encouraging [6].

A phase II trial of a VEGF gene therapy in 105 patients with claudication (leg pain when walking) found no difference in the change in peak walking time.
The phase III TAMARIS trial of an FGF gene therapy enrolled 525 patients with critical limb ischemia, the most severe form of PAD. It found no significant difference in time to major amputation or death.

The reviewers list several reasons for these results [6]:

Only a single-digit percentage of cells took up the introduced genes.
Patients were older and sicker than the animals in preclinical models.
Different routes of giving the treatment were never systematically compared.

Angiogenesis in fat grafting and cell-assisted lipotransfer

A transplanted fat graft has no blood supply at first. Early growth of new vessels into the graft is one factor thought to affect how much of it survives. In 2008, Yoshimura and colleagues reported on cell-assisted lipotransfer (CAL). In this method, the stromal vascular fraction (SVF), a mix of cells that includes adipose-derived stem/stromal cells (ASCs), is taken from part of the harvested fat and added back to the rest before injection [7]. The authors proposed that ASCs might help grafts survive in several ways. They might turn into endothelial cells, or release growth factors that promote angiogenesis. Their study of 40 breast augmentation patients had no control group. The authors wrote that controlled studies and long-term results were needed [7].

A systematic review published in Cureus in 2025 covered 12 clinical studies of grafts enriched with cells. It reported higher volume retention in several of them, including one randomized trial with 80.9% retention versus 16.3% in controls at 4 months. The review found no increase in infection, seroma, oil cysts or cancer recurrence during follow-up [8]. However, it described large differences between studies in methods and outcome measures, and it called for larger long-term randomized trials. It also noted that the included studies gave limited detail on how vessels form in the graft [8]. Better angiogenesis is therefore a proposed mechanism for improved retention, not an established one.

Key points

Angiogenesis builds new vessels from existing ones. Vasculogenesis forms the first vessels in the embryo [2].
VEGF-A is the main signal that switches angiogenesis on [2].
Blocking angiogenesis is an established treatment in some cancers and in wet AMD [1][5].
Stimulating angiogenesis to treat limb ischemia has not yet shown consistent clinical benefit [6].
In fat grafting, the role of angiogenesis is a hypothesis supported by preliminary and heterogeneous clinical evidence [7][8].