Receptor tyrosine kinase-mediated angiogenesis - PubMed (original) (raw)

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Receptor tyrosine kinase-mediated angiogenesis

Michael Jeltsch et al. Cold Spring Harb Perspect Biol. 2013.

Abstract

The endothelial cell is the essential cell type forming the inner layer of the vasculature. Two families of receptor tyrosine kinases (RTKs) are almost completely endothelial cell specific: the vascular endothelial growth factor (VEGF) receptors (VEGFR1-3) and the Tie receptors (Tie1 and Tie2). Both are key players governing the generation of blood and lymphatic vessels during embryonic development. Because the growth of new blood and lymphatic vessels (or the lack thereof) is a central element in many diseases, the VEGF and the Tie receptors provide attractive therapeutic targets in various diseases. Indeed, several drugs directed to these RTK signaling pathways are already on the market, whereas many are in clinical trials. Here we review the VEGFR and Tie families, their involvement in developmental and pathological angiogenesis, and the different possibilities for targeting them to either block or enhance angiogenesis and lymphangiogenesis.

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Figures

Figure 1.

Figure 1.

Schematic presentation of Tie and VEGF receptors and their ligands. There are five VEGFs and three angiopoietins in mammals (the mouse ortholog of Ang4 is also referred to as Ang3). Dotted lines indicate that the ligand–receptor interaction is weak or nonexistent for some isoforms of the ligand (Joukov et al. 1997; Baldwin et al. 2001; Leppanen et al. 2011). CUB, Clr/Cls, urchin EGF-like protein, and bone morphogenetic protein I; CF, coagulation factor; MAM, meprin/A5-protein/PTPμ; Ig, immunoglobulin; EGF, epidermal growth factor; FN, fibronectin.

Figure 2.

Figure 2.

Schematic presentation of the involvement of RTKs in sprouting angiogenesis. VEGF-A and VEGF-C activate VEGFR-2 and VEGFR-3 in the tip cells of angiogenic sprouts, which leads to the migratory cell phenotype. Dll4, which is expressed in the tip cells, interacts with Notch on stalk cells to down-regulate VEGFR-2 and VEGFR-3 and to up-regulate VEGFR-1. Tip cells express Ang2, and may release Ang2 from the Weibel-Palade bodies promoting angiogenesis. Pericyte-produced and matrix-associated Ang1 stabilizes the stalk cells via cell–cell junctional Tie receptor complexes, promoting cell survival, matrix interactions, and endothelial barrier function. In the stalk cells, Ang2 may compete with Ang1, promoting vessel destabilization.

Figure 3.

Figure 3.

Schematic presentation of inhibitors of the VEGF and Tie pathways. Inhibitors approved by the FDA for clinical use are indicated in blue. Inhibitors that are currently tested in clinical trials are indicated in black and preclinical and nonclinical inhibitors in red.

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