The role of VEGF in angiogenesis

By David Bruce, PhD

Vascular endothelial growth factor (VEGF) is a key contributor in the formation of new blood vessels.

VEGF can induce growth of pre-existing (angiogenesis) or de novo vessels (vasculogenesis), and is therefore key for embryonic development and vessel repair. VEGF is also hijacked by solid tumors to support their neoplastic growth.

The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor 1 and 2 (PIGF-1 and PIGF-2, respectively)1,2. VEGF-A is the most potent inducer of blood vessel growth known to date, whereas VEGF-E is more specific for localized pathological processes of angiogenesis.

Family members are encoded by multiple exons that can can give rise different isoforms after alternative splicing, with consequence on solubility and receptor binding3. For example, VEGF-A exists in seven isoforms, while VEGF-B presents two isoforms.

VEGF family members transduce their signal intercellularly by binding to membrane-bound tyrosine kinase receptors: VEGF-A and B have a preference for VEGFR-1; VEGF-A, C, D and E can bind to VEGFR-2; VEGF-C and D to VEGFR-3 (expressed only in hematopoietic cells). The activation of VEGF receptors is considered one of the most critical events in angiogenesis3.

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VEGF signaling pathways

VEGF has activity in diverse cell types, such as muscle4 and neuronal cells5, however its main actions are on endothelial cells6. Family members play key roles in orchestrating the formation of new blood vessels, such as induction of gene expression, regulation of vascular permeability, and promotion of cell migration, proliferation and survival.

These are all induced by the binding of VEGF to VEGF-Rs, and the resulting activation of multiple downstream signaling pathways. These include: the Ras/MAPK pathway to regulate cell proliferation and gene expression; the FAK/paxillin pathway involved in the rearrangement of the cytoskeleton; the PI3K/AKT pathway regulating cell survival; the RhoA/ROCK pathway to form of new capillaries; the PLCγ pathway which controls vascular permeability6,7.


VEGF and the formation of new blood vessels

High levels of VEGF are observed during embryo development, where it cooperates with multiple endothelial growth factors to control the formation of new blood vessels1. As a consequence, disruption of VEGF pathways in mice increases embryonic lethality due to circulatory problems8.

Expression of VEGF decreases significantly after birth. However, localized levels can be up-regulated in tissues undergoing wound healing or fracture repair2. Recent studies have emphasized the role VEGF plays in pathological conditions involving the formation of new blood vessels, such as cancer, rheumatoid arthritis and age-related macular degeneration3,9,10.

Once the angiogenic switch is induced to promote the formation of new blood vessels, a complex and highly regulated sequence of events takes place. By activating multiple proteases, this pathway promotes the degradation of the basement membrane surrounding the existing vessel. This is followed by increased proliferation of endothelial cells, the formation of a lumen and a new basement membrane, and the fusion of newly formed vessels2.


References

  • 1. Gilbert, SF (2000) Developmental biology (6th Edition). Sunderland (MA): Sinauer Associates.
  • 2. Adair, TH and Montani JP (2010) Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.
  • 3. Sullivan LA and Brekken RA (2010) The VEGF family in cancer and antibody-based strategies for their inhibition. MAbs. 2010 Mar-Apr; 2(2): 165–175.
  • 4. Bryan B, Walshe T, Mitchell D, Havumaki J, Saint-Geniez M, Maharaj A, Maldonado A and D'Amore P (2008) Coordinated Vascular Endothelial Growth Factor Expression and Signaling During Skeletal Myogenic Differentiation. Mol Biol Cell. 2008 March; 19(3): 994–1006.
  • 5. Jin K, Mao XO, Greenberg DA. Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J Neurobiol. 2006 Feb 15;66(3):236-42.
  • 6. Lee S, Chen T, Barber C, Jordan M, Murdock J, Desai S, Ferrara N, Nagy A, Roos K and Iruela-Arispe M (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007 August 24; 130(4): 691–703.
  • 7. Zachary I. VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans. 2003 Dec;31(Pt 6):1171-7.
  • 8. Ji Y, Lu X, Zhong Q, Liu P, An Y, Zhang Y, Zhang S, Jia R, Tesfamariam IG, Kahsay AG, Zhang L, Zhu W, Zheng Y (2013). Transcriptional profiling of mouse uterus at pre-implantation stage under VEGF repression. PLoS One. 8(2):e57287.
  • 9. Szekanecz Z, Besenyei T, Paragh G, Koch AE (2009) Angiogenesis in rheumatoid arthritis. Autoimmunity. 42(7):563-73.
  • 10. Foxton RH, Finkelstein A, Vijay S, Dahlmann-Noor A, Khaw PT, Morgan JE, Shima DT, Ng YS (2013) VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. Am J Pathol. 2013 Apr;182(4):1379-90.
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