Table 3.
Endogenous and pharmaceutical compounds that modulate lymphangiogenesis.
| Mechanism of Action | Reference(s) | |
|---|---|---|
| Lymphangiogenesis Activators | ||
| VEGF-A | Directly binds to VEGFR-2 on pre-existing lymphatic cells. Indirectly recruits inflammatory cells that produce VEGF-C and VEGF-D. | 221; 238; 242 |
| VEGF-C and VEGF-D | Directly binds to VEGFR-3 on lymphatic cells. Indirectly stimulates lymphangiogenesis. | 295 |
| PDGFa | A direct lymphangiogenic factor that binds to tyrosine kinase receptors on LECs and induces a signaling pathway similar to VEGF-C binding to VEGFR-3. | 296 |
| bFGFb | bFGF or FGF-2, binds to VEGFR-3 and indirectly stimulates lymphangiogenesis. LYVE-1 can bind to bFGF and inhibit bFGF-dependent lymphangiogenesis. | 35; 256 |
| IGF-1 and IGF- 2c | IGF induces phosphorylation of intracellular signaling factors and extracellular kinases in LECs | 297 |
| HGFd | Mechanism is unknown, but it is believed that HGF can bind to VEGFR-3 and induce lymphangiogenesis. | 298 |
| Ang | Mechanism is unknown, but it is believed that Ang-2 and Ang- 2 induces lymphangiogenesis through binding to its Tie2 receptor. | 299; 300; 301; 302 |
| IRS-1 | Mechanism is unknown, but it is believed that IRS-1 promotes macrophage infiltration, which plays a role in lymphangiogenesis. Inhibition of IRS-1 by GS-101 (Aganirsen) suppresses lymphangiogenesis. | 204; 205; 206 |
| Lymphangiogenesis Inhibitors | ||
| sVEGFR-2 | Binds to VEGF-C and prevents it from binding to VEGFR-3 and inducing lymphangiogenesis. | 196 |
| Class 3 Semaphorins | Binds to Nrp2 on lymphatic cells. Believed to inhibit VEGF-C phosphorylation of VEGFR-3. | 136; 303 |
| Endostatin | Competes with VEGF-C for binding to VEGFR-3. | 291 |
| Vasohibin-1 | Believed to inhibit the pro-lymphangiogenic effects of VEGF- A. | 289; 304 |
| Anti-VEGFR-2 | A neutralizing antibody that directly binds to VEGFR-2 and prevents it from interacting with VEGF-C. | 248; 249 |
| Anti-VEGFR-3 | A neutralizing antibody that binds VEGFR-3 and prevents VEGF-C binding to VEGFR-3. | 254 |
| VEGF trap | A soluble decoy receptor that binds and traps VEGF, preventing it from binding to VEGFR-1 and VEGFR-2 and inducing lymphangiogenesis. | 259; 5; 238; 261 |
| sVEGFR-3 | A soluble receptor that binds to and traps VEGF-C, preventing it from binding VEGFR-3 and inducing lymphangiogenesis. | 266 |
| Canstatin | Inhibits Ang-1–induced lymphangiogenesis. | 271 |
| Lamstatin | Believed to stimulate apoptosis. | 272 |
| 16K N terminal human prolactin | Induces LEC apoptosis. | 273 |
| Small peptide derived from somatotrophin-contained domain | Induces LEC apoptosis. | 274 |
| MMPI270 | Inhibits the actions of MMP2 and MMP9, two pro- lymphangiogenic members of the MMP family. | 276 |
| COX-2 inhibitors | Inhibits the action of COX2 enzymes implicated in lymphangiogenesis. | 280; 281; 46 |
| siRNA | Downregulates VEGF-C expression by gene silencing. | 282 |
| Curcurmin | Believed to inhibit tubule formation through Akt and MMP2 pathways. | 283 |
Note. – PDGF = platelet-derived growth factor; bFGF = basic fibroblast growth factor; IGF = insulin-like growth factor; HGF = hepatocyte growth factor.