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Overview of Angiogenesis

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Angiogenesis is the body’s process of forming new blood vessels from the existing vascular system, in a process commonly referred to as “sprouting.” This differs from vasculogenesis, the initial formation of a vascular system, which occurs during the development of an organism. While angiogenesis typically also takes place during development, adult vascular endothelial cells retain the ability to respond to pro-angiogenic signals.

VEGF and Notch signaling pathways serve complementary but independent roles in the promotion of angiogenesis. Notch signaling is the crucial first step in the process, as it determines the tip and stalk cells driving the formation of the new vessel. The Notch1 receptor ligand Dll4 in particular regulates this process1. Both Notch1 and Dll4 are expressed by vascular endothelial cells, and crosstalk between endothelial cells in the vessel sprout via this pathway acts as a negative regulatory mechanism to control the number of tip cells (i.e. new vessel sprouts) by dampening the cellular response to VEGF2,3. VEGF, in turn, promotes the continued development of the new vessel via VEGFR2 signaling in adults, a process which can be counter-regulated by VEGFR1 signaling in stalk cells4. The primary VEGF ligand driving this response is VEGFA, which can bind both of the aforementioned VEGF receptors. VEGFA binding to VEGFR2 promotes cell proliferation, migration, and survival5, while its binding to VEGFR1 acts as a sink as the binding affinity between this receptor-ligand pair is approximately ten-fold higher than VEGFA-VEGFR26. The VEGF superfamily contains several other receptors and ligands, which play additional but less well-defined roles in angiogenesis (and other developmental processes)7.

Regulation of angiogenesis is crucial for preventing or compensating for ischemic conditions, as tissue can only survive within approximately 1-2 mm of a blood vessel8,9. Hypoxic conditions can drive the upregulation of pro-angiogenic factors such as VEGF10, which acts as a regulatory mechanism to maintain oxygen levels in ischemic states such as myocardial infarction, but can also promote tumor progression11. Indeed, developing tumors require neoangeogenesis in order to survive, and as such, anti-angiogenic therapies have been used in the clinic to target this disease12. Several of these treatments have shown clinical success in cancers including non-small cell lung cancer, metastatic colorectal cancer, and ovarian cancer, either as single agents or in combination with chemotherapy. However in other tumor types such as metastatic melanoma, pancreatic cancer, and prostate cancer, the efficacy of anti-angiogenic therapies has been less promising12. Furthermore, refractory tumor growth following anti-angiogenic therapy - even after an initial response - is extremely common13. However, even the partial success of anti-angiogenic therapies in cancer has proven much more successful than trying to do the opposite in ischemic disease: there are currently no pro-angiogenic therapies on the market14, although a few show promise in preclinical models15,16.


Detection of human CD31 (red) in FFPE breast adenocarcinoma by IF

Detection of human CD31 (red) in FFPE breast adenocarcinoma by IF.  Antibody: Rabbit anti-CD31 (IHC-00055).  Secondary: DyLight® 594-conjugated goat anti-rabbit IgG (A120-201D4). Counterstain: DAPI (blue).

Detection of human Nucleolin in FFPE stomach adenocarcinoma by IHC

Detection of human Nucleolin in FFPE stomach adenocarcinoma by IHC. Antibody: Rabbit anti-Nucleolin (IHC-00083). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Localization of human HIF1-alpha binding sites in immunoprecipitates from CoCl2 treated HepG2 lysates by ChIP-Seq

Localization of human HIF1-alpha binding sites in immunoprecipitates from CoCl2 treated HepG2 lysates by ChIP-Seq. Antibody: Rabbit anti-HIF1-alpha recombinant monoclonal [BL-124-3F7] (A700-001).


Below is the entire list of targets involved in Angiogenesis research. Can’t find what you are looking for? Bethyl offers a custom antibody service.



1. Phng L-K, Gerhardt H. 2009. Angiogenesis: a team effort coordinated by notch. Dev Cell. Feb;16(2):196–208.

2. Hellström M, Phng L-K, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, et al. 2007. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. Feb 15;445(7129):776–780.

3. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ. 2007. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A. National Academy of Sciences, Feb 27;104(9):3219–3224.

4. Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM, Rosewell I, Busse M, Thurston G, Medvinsky A, et al. 2010. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol. Oct;12(10):943–953.

5. Abhinand CS, Raju R, Soumya SJ, Arya PS, Sudhakaran PR. 2016. VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J Cell Commun Signal. Springer; Dec;10(4):347–354.

6. Shibuya M. 2006. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis. 9(4):225–230.

7. Cébe-Suarez S, Zehnder-Fjällman A, Ballmer-Hofer K. 2006. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. Mar;63:601–615.

8. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. 2006. Vasc Health Risk Manag. Sept;2(3):213–219.

9. Griffith CK, Miller C, Sainson RCA, Calvert JW, Jeon NL, Hughes CCW, George SC. 2005. Diffusion Limits of an in Vitro Thick Prevascularized Tissue. Tissue Eng. Jan-Feb;11(1-2):257–266.

10. Semenza GL. 2012. Hypoxia-inducible factors in physiology and medicine. Cell. Feb 3;148(3):399–408.

11. Semenza GL. 2000. HIF-1 and human disease: one highly involved factor. Genes Dev. Aug 15;14(16):1983–1991.

12. Vasudev NS, Reynolds AR. 2014. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. Jul;17(3):471–494.

13. Bergers G, Hanahan D. 2008. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. Aug;8(8):592–603.

14. Briquez PS, Clegg LE, Martino MM, Gabhann F Mac, Hubbell JA. 2016. Design principles for therapeutic angiogenic materials. Nat Rev Mater. 2016;1:15006.

15. Ben-Ami R, Albert ND, Lewis RE, Kontoyiannis DP. 2013. Proangiogenic Growth Factors Potentiate In Situ Angiogenesis and Enhance Antifungal Drug Activity in Murine Invasive Aspergillosis. J Infect Dis. Apr 1;207(7):1066–1074.

16. Ali Z, Islam A, Sherrell P, Le-Moine M, Lolas G, Syrigos K, Rafat M, Jensen LD. 2018. Adjustable delivery of pro-angiogenic FGF-2 by collagen-alginate microspheres. Biol Open. Feb 15;027060. [Epub ahead of print]