Almost every tissue in the body needs a blood supply within a fraction of a millimetre, and when tissue grows or heals, new vessels must sprout from old ones. That process, angiogenesis, is steered above all by one signalling protein: vascular endothelial growth factor, or VEGF. It is central to wound healing, to eye disease and to cancer, which is why drugs that block it are among the most widely used in medicine, and why research peptides reported to promote it deserve careful reading.
The short answer
- Angiogenesis is the growth of new blood vessels from existing ones. VEGF-A is its main signal.
- The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor. They act on three receptor tyrosine kinases: VEGFR1, VEGFR2, the main driver of angiogenesis, and VEGFR3, which mainly guides lymphatic vessels.
- VEGF was discovered twice: as a vascular permeability factor in 1983 and as an endothelial growth factor in 1989.
- Blocking VEGF is an established treatment strategy, from the cancer drug bevacizumab, first approved in 2004, to anti-VEGF eye injections for wet macular degeneration.
- Several research peptides, including BPC-157, thymosin beta-4 (the basis of TB-500), LL-37 and GHK-Cu, have been reported to promote angiogenesis in cell and animal studies. That is why wound researchers study them, and why the cancer question matters.
How new vessels form
In the embryo, the first blood vessels assemble from scratch, a process called vasculogenesis. After that, most new vessels form by angiogenesis: existing vessels sprout branches. When tissue runs short of oxygen, cells switch on a sensor called HIF-1, which turns on the VEGF gene. VEGF diffuses out and reaches nearby vessels, where it prompts one endothelial cell to become a “tip cell” that migrates toward the signal, followed by “stalk cells” that divide to form the new tube.
VEGF and its receptors
| Receptor | Also called | Main role |
|---|---|---|
| VEGFR1 | Flt-1 | Binds VEGF-A, VEGF-B and placental growth factor; partly acts as a decoy that fine-tunes signalling |
| VEGFR2 | KDR or Flk-1 | The main driver of endothelial cell growth, migration and new vessel formation |
| VEGFR3 | Flt-4 | Binds VEGF-C and VEGF-D; guides lymphatic vessels |
Unlike the G protein-coupled receptors that most peptide hormones use, VEGF receptors are enzymes: when VEGF binds, they tag each other with phosphate groups and set off signalling cascades inside the cell. Our guide to how peptide receptors work explains the difference between receptor families.
How VEGF was discovered
- 1971Judah Folkman proposes that tumours depend on new blood vessels and that blocking angiogenesis could treat cancer.
- 1983Harold Dvorak’s group reports that tumour cells secrete a “vascular permeability factor” that makes vessels leaky.
- 1989Napoleone Ferrara at Genentech isolates an endothelial cell growth factor and names it VEGF. It turns out to be the same molecule.
- 2004Bevacizumab, an antibody against VEGF-A, becomes the first approved anti-angiogenic cancer drug in the United States.
- 2019William Kaelin, Peter Ratcliffe and Gregg Semenza share the Nobel Prize for discovering how cells sense oxygen, the switch that controls VEGF.
Blocking and boosting angiogenesis
Blocking VEGF has become routine medicine. Anti-VEGF antibodies and related drugs are used in several cancers, and injections into the eye have transformed the treatment of wet age-related macular degeneration, in which leaky new vessels damage the retina.
Boosting angiogenesis has proved much harder. Early attempts to grow new vessels with VEGF in people with poor blood flow to the heart or legs produced mixed and largely disappointing results, partly because new vessels need to mature and stabilize, not just sprout. That history is a useful caution for any compound described as pro-angiogenic.
Tissue-repair research peptides with Janoshik certificates.
Browse recovery and repairPeptides in angiogenesis research
| Peptide | Reported effect | Evidence | Our guide |
|---|---|---|---|
| BPC-157 | Increased VEGFR2 expression and activated the VEGFR2–Akt–eNOS pathway | Rat hind-limb ischaemia and endothelial cell studies (2017) | BPC-157 guide |
| Thymosin beta-4 (TB-500) | Promoted endothelial cell migration and vessel formation | Cell and rat wound-healing studies | TB-500 guide |
| LL-37 | Stimulated endothelial cells through the formyl peptide receptor FPRL1 | Cell and animal studies (2003) | LL-37 guide |
| GHK-Cu | Reported to raise VEGF and other growth-factor expression | Mainly cell studies | GHK-Cu guide |
One detail is easy to miss. In the 2017 BPC-157 study, the peptide increased VEGFR2, the receptor, but not VEGF-A itself, in the endothelial cells tested. Precise claims like that are more useful than the general label “pro-angiogenic”.
BPC-157VEGFR2-pathway researchView product and COA
LL-37Angiogenic host-defence peptideView product and COA
GHK-CuCopper tripeptideView product and COA
The cancer question
Tumours need new blood vessels to grow beyond a small size, which is the whole basis of anti-VEGF cancer therapy. It follows that a compound which promotes angiogenesis could, in principle, help a tumour as well as a wound. Reviewers of the BPC-157 literature have raised exactly this point, noting that most of its studies come from a single research group and that its pharmacology in people has not been properly characterized. No study has shown that these peptides cause cancer, but the question has not been tested, and it is one of the reasons research peptides are not medicines.
Reasonably well established
- VEGF-A acting through VEGFR2 is the main driver of angiogenesis.
- Blocking VEGF works as a treatment in several cancers and eye diseases.
- Low oxygen controls VEGF through the HIF system.
Open questions
- Whether peptide effects seen in animals translate to people.
- How to promote stable, mature vessels rather than leaky sprouts.
- The long-term safety of sustained pro-angiogenic signalling.
Research use only. Pure Peptides Canada products are laboratory reagents, not for human or veterinary use. This article summarizes published research for education and is not medical advice; nothing here suggests that any product treats any condition.
Frequently asked questions
What is angiogenesis?
Angiogenesis is the growth of new blood vessels from existing ones. It happens during growth, wound healing and the menstrual cycle, and it is also exploited by tumours and drives some eye diseases.
What does VEGF do?
Vascular endothelial growth factor signals to the cells lining blood vessels, making them divide, migrate and form new vessels, and making vessels more permeable. Its production rises when tissue is short of oxygen.
What are the VEGF receptors?
There are three: VEGFR1 (Flt-1), which partly acts as a decoy; VEGFR2 (KDR or Flk-1), the main driver of angiogenesis; and VEGFR3 (Flt-4), which mainly guides lymphatic vessels. All three are receptor tyrosine kinases.
Why do cancer drugs block VEGF?
Tumours need new blood vessels to grow beyond a small size. Blocking VEGF, for example with the antibody bevacizumab, starves tumours of new vessel growth, and anti-VEGF drugs are used in several cancers and eye diseases.
Does BPC-157 increase VEGF?
In a 2017 study in rats and cultured endothelial cells, BPC-157 increased the expression of VEGFR2, the main VEGF receptor, and activated its signalling pathway, but did not increase VEGF-A itself. The evidence is from animal and cell studies, not human trials.
Is promoting angiogenesis always good?
No. New vessels help wounds heal, but they also feed tumours and damage the eye in wet macular degeneration. That is why pro-angiogenic compounds raise safety questions that have to be tested, not assumed.
Tissue-repair research, with the evidence in view
BPC-157, LL-37 and GHK-Cu with Janoshik certificates, priced in Canadian dollars and shipped tracked from inside Canada.
References
- Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186.
- Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–985.
- Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851–858.
- Hsieh MJ, Liu HT, Wang CN, et al. Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med. 2017;95(3):323–333. Springer
- Koczulla R, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111:1665–1672.
- Malinda KM, et al. Thymosin beta4 accelerates wound healing. J Invest Dermatol. 1999;113:364–368.
For laboratory research use only. Not for human or veterinary use. This article is educational and is not medical advice.