Angiogenesis

Angiogenesis is the construction of new blood vessels from pre-existing ones. Angio
means vessel, referring to blood vessels while genesis means formation. Being one of
the most vital processes in the human body which forms the lining inside the blood
vessels, it is important for the process to run smoothly. The process is made up of the
relocation, growth and differentiation of endothelial cells lining the blood vessels and is
controlled by chemical signals in the body. It occurs in both health and disease and is
vital as capillaries are needed for the diffusion exchange of nutrients and metabolites.
Furthermore, it is specifically controlled by proangiogenic factors and antiangiogenic
factors such as inhibitors.

There are 2 types of angiogenesis: sprouting and intussusceptive. The initiation of

sprouting angiogenesis occurs when a level of hypoxia is detected in poorly supplied
tissues by mechanisms that sense the amount of oxygen that is contained. To satisfy
the metabolic requirements of parenchymal cells, this further demands for the formation
of new blood vessels. The way in which the parenchymal cells respond to a hypoxic
environment, is by secreting a particular proangiogenic growth factor called vascular
endothelial growth factor (VEGF). VEGF signals bind to receptors on the membrane of
standard epithelial cells. Signals are produced to trigger the growth and viability of new
blood vessels, when VEGF alongside other endothelial growth factors bind to their
receptors on endothelial cells. However, certain chemical signals may act as inhibitors
and impede the angiogenesis process. This further will start to affect the growth and
condition of the blood vessels if the chemical signals become skewed towards either
side of the inhibiting or stimulating effects of the signals, which is vital during healing
and growth. On the other hand, intussusceptive angiogenesis is the quicker and more
efficient type of angiogenesis as it initially only requires the reorganization of existing
endothelial cells. A single vessel splits in two as the vessel wall extends into the lumen.
The intussusceptive growth plays a crucial role in the pruning of larger micro vessels
alongside the formation of artery and vein bifurcations. During vascular development in
embryos, intussusceptive angiogenesis is important due to the limited resources
alongside fast speed of growth. However, when compared to sprouting angiogenesis,
intussusceptive angiogenesis is poorly understood due to it being discovered more
recently in 1986 (Adair and Montani, 2010).

Angiogenesis occurs in both pathological processes such as during the healing of

wounds, alongside physiological states such as the development of early embryos.
During the healing of wounds, a microvascular network is created throughout the
granulation tissue as angiogenic capillary sprouts permeate the fibrin rich areas of the
wound clot, within a short period of time (Clark, Tonnesen and Feng, 2000). The growth
of tumours is also caused by an angiogenic switch where the tumour overexpresses
angiogenic factors such as VEGF, which allows them to make the switch. On the other
hand, during the development of embryos the VEGF system regulates embryonic
development. The expansion of the vascular tree occurs due to the sprouting action of
the endothelial cells of existing blood vessels, further creating new blood vessels during
growth (Simionescu, D. and Simionescu, A., 2011). This further reiterates the fact that
the process is both beneficial and detrimental in the human body.

Angiogenesis has a strong link to cancer and the growth of tumours. It is required for
metastasis and is vital for its progression. A lack of blood supply causes severe
restrictions to avascular tumours and is the reason why tumours must make an
angiogenic switch to be able to continue to grow (Folkman, 2002). The most common
antiangiogenic treatment is the development of antiangiogenic agents by inhibition of
proangiogenic factors. The use of endogenous angiogenic inhibitors such as endostatin
and angiostatin, control the growth of tumours by reversing the angiogenic switch and
interfering with pro-angiogenic activity factors such as VEGF (Javaherian et al, 2010).
Similarly, the drug Avastin is a recombinant humanized monoclonal antibody formerly
known as Bevacizumab, first made specifically, for the treatment of metastatic colorectal
cancer (mCRC). It is proven to be a well-tolerated and effective method of therapy for
mCRC when combined with chemotherapy and is known to increase the efficacy while
controlling the amount of negative side effects, making it the rational approach for
treatment (Shih and Lindley, 2006).
A specific area where angiogenesis is actively working positively, is during high intensity
training. New blood vessels are formed as their growth is induced by endurance
training. However, the intensity and type of training is what the effect depends on. Type
I and type II muscle fibres have been shown to increase equally during exercise at both
moderate and high intensity levels of training. During moderate intensity training, mostly
type I muscle fibres are engaged, whereas during high intensity training type II muscle
fibres are activated. This results in an increase in the number of capillaries of this type
of muscle fibre (Jensen, Bangsbo and Hellsten, 2004). A study to find the effect of high
intermittence endurance training on the distribution of VEGF and basic fibroblast growth
factor (bFGF) (D’Amore and Ku, 1995) using hybridization of human muscle found that
after just 7 days of one-legged exercise training, the expression of VEGF messenger
RNA had increased drastically between and within skeletal muscle fibres. With another
study showing that after 3 to 4 days of electrical stimulation, the VEGF protein had
increased in the matrix between the endothelial cells and muscle cells, when looking at
an immunohistochemical analysis in rodents (Jensen, Bangsbo and Hellsten, 2004).
Therefore, angiogenesis is essential for athletes specifically who highly rely on their
muscles. The higher the intensity of training, the higher the amount of VEGF resulting in
a higher number of capillaries. This allows for a greater amount of blood and proteins to
reach the muscle cells while allowing for a higher amount of diffusion of nutrients.

To conclude, Angiogenesis has a vital role in the growth and development of our bodies
as a whole. However, it can be detrimental if it works adversely, as presented through
the growth of cancer tumours. Despite its abilities to work negatively, it also plays a
major fundamental role in biological processes within our bodies such as the
development of embryos, growth of new capillary blood vessels and wound healing. Its
treatment has been very highly developed in recent years and has shown great
success. However, anticancer therapy treatment methods are still under continuous
intensive clinical trials while research is continuing to find new and improved methods
which prove to be even more efficient and have even less negative side effects.
References

Adair, T.H., Montani, J. (2010) Angiogenesis. London: Morgan & Claypool Life
Sciences. Available at: https://www.ncbi.nlm.nih.gov/books/NBK53242/ (Accessed: 17
December 2019)

Clark, A.F.R., Tonnesen, M.G. and Feng, X. (2000) Angiogenesis in Wound Healing,
Journal of Investigative Dermatology Symposium Proceedings, 5(1), pp. 40-46

D’Amore, P.A. and Ku, P. (1995) Regulation of basic fibroblast growth factor (bFGF)
gene and protein expression following its release from sublethally injured endothelial
cells, Journal of cellular Biochemistry, 58(3). Doi: https://doi.org/10.1002/jcb.240580307

Folkman, J. (2002) Role of angiogenesis in tumour growth and metastasis, Seminars in

Oncology, 29(6), pp.15-18.

Jensen, L., Bangsbo, J. and Hellsten, Y. (2004) Effect of high intensity training on
capillarization and presence of angiogenic factors in human skeletal muscle, The
journal of Physiology, 557(2), pp. 571-582. Doi:
https://doi.org/10.1113/jphysiol.2003.057711

Javaherian, K. et al. (2010) Two Endogenous Antiangiogenic Inhibitors, Endostatin and

Angiostatin, Demonstrate Biphasic Curves in their Antitumor Profiles, Dose-Response,
9(3). Doi: https://doi.org/10.2203%2Fdose-response.10-020.Javaherian

Simionescu, D. and Simionescu, A. (2011) Vasculogenesis and Angiogenesis from

Embryonic Development to Regenerative Medicine. London: IntechOpen. Available at:
https://www.intechopen.com/books/vasculogenesis-and-angiogenesis-from-embryonic-
development-to-regenerative-medicine (Accessed: 16 December 2019).

Shih, T. and Lindley, C. (2006) Bevacizumab: An angiogenesis inhibitor for the treatment
of solid malignancies, Clinical Therapeutics, 28(11), pp.1779-1802. Doi:
https://doi.org/10.1016/j.clinthera.2006.11.015