Angiogenesis

Angiogenesis is defined as the physiological process by which new blood vessels are formed from pre-existing blood vessels. It is a critical process that enables development, skeletal muscle hypertrophy, menstruation, pregnancy, and wound healing, but which also contributes to pathological conditions including neovascular disorders (eg, retinopathy), rheumatoid arthritis, psoriasis, AIDS/Kaposi sarcoma, and cancer (tumorigenesis). Angiogenesis is a complex and highly ordered process that relies upon extensive signaling networks both among and within endothelial cells (ECs), their associated mural cells (vascular smooth muscle cells [VSMCs] and pericytes) and other cell types (eg, immune cells).

Vascular endothelial growth factor (VEGF) is a family of proteins that are required for angiogenesis. There are multiple isoforms of VEGF, including VEGF-A, VEGF-B, VEGF-C, and VEGF-D, each playing a major role in different angiogenic contexts ranging from embryonic to lymphatic angiogenesis. VEGF-A is the principal mediator of angiogenesis. Alternative splicing produces 4 main VEGF-A isoforms of different lengths-121, 165, 189, and 206 amino acids long-which display varying affinities for heparan sulfate proteoglycans (HSPG). The balance between freely diffusible and HSPG-bound VEGF-A results in a gradient, leading to the formation of a pioneering tip cell-an endothelial cell that responds to angiogenic signaling. The tip cell creates the leading edge of the angiogenic sprout and eventually vascular branching through various steps of cell migration. The branches first expand with site-specific metabolic demands and is then subdivided into arteries, capillaries, veins, and lymphatic vessels, a process mediated by the Notch-Gridlock, Ephrin-B2/EphB4, and Sonic Hedgehog (SHH) pathways. With further vessel maturation and hemodynamic changes, ECs secrete platelet-derived growth factor (PDGF)-B to recruit pericytes and VSMCs. These mural cells, via expression of angiopoietin-1 (ANG-1), bind to ECs, resulting in TGF-β activation and extracellular matrix (ECM) deposition, thereby stabilizing the growing vascular bed. Downstream effectors-including phosphatidylinositol-3 kinase (PI3K), Src kinase, focal adhesion kinase (FAK), p38 mitogen-activated protein kinase (p38 MAPK), Smad2/3, and phospholipase C gamma (PLCγ)/Erk1/2-promote EC survival, vascular permeability, and migratory/proliferative phenotypes. Positive and negative transcriptional regulation of these moieties via microRNAs (miRNAs) further influence postnatal angiogenesis. Specifically, miR-126 has been shown to play a vital role, as deletion leads to defective vessel formation and embryonic lethality.

Pathological and physiological angiogenesis share many similarities in terms of signaling events and the resulting changes to cell function and behavior and, therefore, may be novel therapeutic options to combat disease. However, a key difference is that pathological vessel development is not terminated upon adequate tissue perfusion. Such uncontrolled, disorganized, unresolved growth precludes advancement of novel angiogenesis-disrupting agents.

Selected Reviews:

• Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 8, 464-78.
• Chung AS, Lee J, Ferrara N (2010) Targeting the tumor vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 10, 505-14.
• Fraisl P, Mazzone M, Schmidt T, Carmeliet P (2009) Regulation of angiogenesis by oxygen and metabolism. Dev Cell. 16, 167-79.
• Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, et al. (2002) VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 417, 954-58.
• Gustafsson E, Fassler R (2000) Insights into extracellular matrix functions from mutant mouse models. Exp Cell Res. 261, 52-68.
• Holderfield MT, Hughes CC (2008) Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-β in vascular morphogenesis. Circ Res. 102, 637-52.
• Jain RK (2003) Molecular regulation of vessel maturation. Nat Med. 9, 685-93.
• Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 246, 1306-9.
• Metcalf D (1989) The molecular control of cell division, differentiation commitment, and maturation in haematopoietic cells. Nature. 339, 27-30.

We would like to thank Diane Bielenberg, PhD, Harvard Medical School, Boston Children’s Hospital, Boston, MA for reviewing this diagram.

created September 2008

revised September 2018