What is Angiogenesis?

Angiogenesis

Angiogenesis is the formation of new blood vessels. It is the process by which the body forms new blood vessels from existing ones. This process occurs throughout the life of an individual, starting in the uterus and continuing to old age. Angiogenesis occurs both in healthy tissues as well as in diseased ones, such as in cancer cell growths.

Why Does Angiogenesis Occur in the Body?

Angiogenesis takes place when a particular body part or tissue requires the supply of nutrients and to it. In hypoxia tissues, the need for oxygen supply to the parenchymal cells is detected by the oxygen sensing mechanisms, which then demands the formation of new blood vessels to meet this need.

Types of Angiogenesis

There are two types of angiogenesis, they are:

  1. Sprouting angiogenesis
  2. Intrussusceptive angiogenesis

Both sprouting and intrussusceptive angiogenesis, occur in the uterus and in adults.

Sprouting Angiogenesis (SA)

Sprouting angiogenesis is the process of growing new blood capillary vessels from pre-existing ones. When this occurs, the new blood vessels shall provide oxygen to expanding tissues and organs.

Sprouting angiogenesis plays important roles in many diseases, such as diabetes, rheumatoid arthritis, cardiovascular ischemic complications and cancer. In cancer, SA is involved not only in primary tumor but also in metastasis formation and further outgrowth of metastasis.

Steps in Sprouting Angiogenesis

Sprouting angiogenesis involves several steps, which include:

  1. Initiation of growth factors responsible for angiogenesis by low oxygen tension, low pH and high lactate levels.
  2. Expression of a transcription factor, hypoxia-inducible factor (HIF), by endothelia cells, which regulates expression of vascular endothelia growth factor (VEGF) and stimulates angiogenesis.
  3. Binding of growth factors to their receptors on endothelia cells and activating them. This is followed by detachment of pericytes.
  4. Binding of VEGF to its receptors and inducing a signaling cascades which enables one endothelia cell to form a tip cell while adjacent cells form stalk cells.
  5. Tip cells express VEGFR, delta-like ligand-4 (DLL-4), and matrix metalloproteinases (MMPs). They form filopodia, which are slender protrusions of the plasma membrane containing parallel bundles of actin filaments.
  6. Rhoa, Racl and Cdc42, members of Rho small GTPases, regulate the formation of filopodia.
  7. Activation of VEGFR leads to the extension of filopodia and migration of the tip cells forward.
  8. Activated endothelia cells secrete proteases, which are essential for the degradation of basement membrane. They allow tip cells to escape from the parent vessels and allow formation of sprouts and guidance of sprouts through the extracellular matrix (ECM).

Intrussusceptive Angiogenesis (IA)

In intrussusceptive angiogenesis, also called splitting angiogenesis, the blood vessel wall extends into the lumen, thereby causing a single vessel to split into two. It is fast and efficient compared to SA. This is because IA only requires reorganization of the existing endothelia cells; it does not rely on endothelia proliferation and migration. Like SA, however, IA also occur throughout the life of an individual, but it plays prominent roles in vascular development in embryos, where growth is fast with limited resources.

Promoters of Angiogenesis

Angiogenesis is regulated by a balance between pro-angiogenic and anti-angiogenic factors. The promoters include, HIF-1, VEGF, FGF, PDGE, TGF-β and angiopoietin and proteases.

Hypoxia-induced Factor-1 (HIF-1)

This is the most potent inducer of the expression of genes such as those encoding for glycolytic enzymes, VEGF and erythropoietin. HIF-1 is upregulated in hypoxia tumor cells; it activates transcription of target genes by binding to Cis-actin enhancers, hypoxia response element (HRE) close to the promoters of those genes.

Vascular Endothelia Growth factor (VEGF)

VEGF functions in angiogenesis by inducing the expression of DLL-4 in tip cells. It promotes the migration of endothelia cells by inducing expression of intergrins. It also stimulates production of MMPs, plasminogen activator and proteolytic enzymes by endothelia cells, which in turn promote the degradation of ECM.

Fibroblast Growth Factor (FGF)

FGF promotes proteases production and upregulates VEGF expression by endothelia cells. It also stimulates endothelia cells proliferation and migration.

Inhibition of Angiogenesis by Thymoquinone

Thymoquinone exerts its inhibitory effects on VEGF, FGF, PIGF, PDGF, which are pro-angiogenic factors, by suppressing the Akt/ERK signaling pathway.

 

REFERENCES

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Martin, A., Komada, M. R., & Sane, D. C. (2003). Abnormal angiogenesis in diabetes mellitus. Medicinal Research Reviews, 23, 117–145.

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Cao, Y., Hong, A., Schulten, H., & Post, M. J. (2005). Update on therapeutic neovascularization. Cardiovascular Research, 65, 639–648.

Carmeliet, P. (2005). Angiogenesis in life, disease and medicine. Nature, 438, 932–936.

Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.

Kerbel, R. S. (2000). Tumor angiogenesis: Past, present and the near future. Carcinogenesis, 21, 505–515.

Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y, Sethi G, Aggarwal BB, Liu M. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008 Jul;7(7):1789-96.