Angiogenesis

Angiogenesis, the formation of new blood vessels, is triggered in response to hypoxia (low oxygen levels in tissues). Angiogenesis happens throughout life as it is necessary for organ development, wound healing, tissue repair, fetal development, menstruation, muscle growth, and other vital physiological functions.

Angiogenesis is strictly coordinated, involving a series of cellular events, including blood vessel initiation, formation, maturation, remodeling, and regression (1). Ideally, it only occurs when and where needed, relying on the balance of pro-angiogenic and anti-angiogenic factors (2). However, an imbalance in angiogenic modulators causes an angiogenic switch that results in excess blood vessel formation (3).

This angiogenic switch happens with increased activity of pro-angiogenic factors over anti-angiogenic factors. It may lead to the growth and spread of malignant tumors, making pathological angiogenesis critical to cancer pathogenesis (4). Dysregulated angiogenesis may also contribute to the pathogenesis of other conditions like immune diseases, cardiovascular diseases, diabetic retinopathy, and age-related macular degeneration (2).

Angiogenesis is primarily grouped into sprouting and intussusceptive angiogenesis. Sprouting angiogenesis describes the growth of new blood vessels induced by angiogenic factors, like vascular endothelial growth factor (VEGF), and occurs when endothelial cells sprout from existing blood vessels and move toward the angiogenic signal. Intussusceptive angiogenesis is a less-understood type of angiogenesis. With this type, new blood vessels form from the splitting of existing ones. These new blood vessels expand and remodel an immature capillary plexus. Intussusceptive angiogenesis may be initiated by angiogenic factors, including VEGF and platelet-derived growth factor (PDGF) (5,6).

Angiogenesis requires the interaction and coordinated execution of signaling pathways, such as the VEGF and PDGF pathways (7). The VEGF pathway, in particular, has been described as one of the most potent signaling pathways regulating physiological and pathological angiogenesis. VEGF is also the most investigated pro-angiogenic factor (8).

The VEGF family of genes includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). VEGF-A is well-established as a critical regulator of blood vessel formation (9). VEGF-B may indirectly promote blood vessel growth by influencing VEGF-A (10). VEGF-C and VEGF-D may mediate angiogenesis during embryogenesis but are primarily involved in lymphangiogenesis, lymphatic growth that occurs when new lymphatic vessels are made from existing ones (11). The role of PIGF in angiogenesis is uncertain, as it has been thought to have both pro and anti-angiogenic properties (6).

Overall, VEGF signaling through VEGFR-1 and VEGFR-2 receptor activation supports many stages of angiogenesis, including angiogenesis initiation, endothelial cell growth, migration, proliferation, and survival, vascular permeability, and tube formation. The VEGF pathway also works in concert with other modulatory pathways, including angiopoietin-Tie and the Notch pathway (9).

In addition to VEGF signaling, Interleukin 8 (IL-8) signaling is involved in the multi-step process of angiogenesis. IL-8 is a pro-inflammatory chemokine in the CXC family. It is released by macrophages, endothelial cells, epithelial cells, and airway smooth muscle cells. IL-8 binds to chemokine receptors, CXCR1 and CXCR2, to perform pro-angiogenic activities such as inducing endothelial cell proliferation, migration, and survival (12).

The PDGF family comprises four genes, PDGF-A, PDGF-B, PDGF-C, and PDGF-D, all involved in angiogenesis (13). Released by endothelial cells, fibroblasts, smooth muscle cells, and glia, PDGF binds to two cell-surface tyrosine kinase receptors, PDGF receptor α, and PDGF receptor β, to initiate angiogenic signals. PDGF supports endothelial cell proliferation and migration, tube formation, vessel maturation and stabilization through pericyte proliferation and recruitment, and upregulation of VEGF, all of which are requisite steps in angiogenesis (6).

Because the dysregulation of these signaling pathways, as well as others like the angiopoietin-Tie signaling pathway and the Notch pathway, is linked to angiogenesis-dependent diseases such as cancer, rheumatoid arthritis, and psoriasis, researchers have explored the clinical benefit of creating antiangiogenic-therapies that target these signaling pathways (15). For instance, targeting VEGF and related signaling pathways has been shown to increase survival outcomes and lifespan of patients with cancer and to prevent blindness in patients with eye diseases (11).

References

1. Staton CA, Reed MW, Brown NJ. A critical analysis of current in vitro and in vivo angiogenesis assays. Int J Exp Pathol. 2009;90(3):195-221.

2. Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. 2023;8(1):198. Published 2023 May 11.

3. ScienceDirect https://www.sciencedirect.com/topics/medicine-and-dentistry/angiogenesis (accessed July 21, 2023)

4. Mabeta P, Hull R, Dlamini Z. LncRNAs and the Angiogenic Switch in Cancer: Clinical Significance and Therapeutic Opportunities. Genes (Basel). 2022;13(1):152. Published 2022 Jan 15.

5. Eelen G, Treps L, Li X, Carmeliet P. Basic and Therapeutic Aspects of Angiogenesis Updated. Circ Res. 2020;127(2):310-329.

6. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2020;77(9):1745-1770. doi:10.1007/s00018-019-03351-7

7. Zhang Y, Wang H, Oliveira RHM, Zhao C, Popel AS. Systems biology of angiogenesis signaling: Computational models and omics. WIREs Mech Dis. 2022;14(4):e1550.

8. Joo YY, Jang JW, Lee SW, et al. Circulating pro- and anti-angiogenic factors in multi-stage liver disease and hepatocellular carcinoma progression. Sci Rep. 2019;9(1):9137. Published 2019 Jun 24.

9. Shibuya M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer. 2011;2(12):1097-1105.

10. Lal N, Puri K, Rodrigues B. Vascular Endothelial Growth Factor B and Its Signaling. Front Cardiovasc Med. 2018;5:39. Published 2018 Apr 20.

11. Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019;176(6):1248-1264.

12. Loizzi V, Del Vecchio V, Gargano G, et al. Biological Pathways Involved in Tumor Angiogenesis and Bevacizumab Based Anti-Angiogenic Therapy with Special References to Ovarian Cancer. Int J Mol Sci. 2017;18(9):1967. Published 2017 Sep 14.

13. ScienceDirect https://www.sciencedirect.com/topics/neuroscience/interleukin-8#:~:text=IL%2D8%20(CXCL%2D8,smooth%20muscle%20cells%20%5B189%2C190%5D. (accessed July 21, 2023)

14. Raica M, Cimpean AM. Platelet-Derived Growth Factor (PDGF)/PDGF Receptors (PDGFR) Axis as Target for Antitumor and Antiangiogenic Therapy. Pharmaceuticals (Basel). 2010;3(3):572-599. Published 2010 Mar 11.

15. Yoo SY, Kwon SM. Angiogenesis and its therapeutic opportunities. Mediators Inflamm. 2013;2013:127170.