Table 2.
Lymphangiogenic and Anti-lymphangiogenic Factors
| Experimental model | Remarks | Reference | |
|---|---|---|---|
| Lymphangiogenic factors | |||
| VEGF-A | Mouse corneal lymphangiogenesis | VEGF-A recruits macrophages, which promote lymphangiogenesis by secreting VEGF-C/VEGF-D. | 103 |
| Mouse subcutaneous immunization model | VEGF-A expression is upregulated concomitantly with lymphangiogenesis in LNs of immunized mice. | 117 | |
| Oxazolone sensitized delayed-type hypersensitivity in mouse ear | Systemic blockade of VEGF-A attenuates lymphangiogenesis in draining LNs. | 181 | |
| HSV-1 infection of cornea | HSV-1 causes lymphangiogenesis by promoting infected cells to secrete VEGF-A. | 182 | |
| VEGF-C, VEGF-D | VEGF-C transgenic mouse | VEGF-C promotes LyEC proliferation and LV enlargement in the skin. | 6 |
| Isolated LyEC | VEGF-C stimulates survival, growth, and migration of LyEC. | 91 | |
| FGF-2–induced corneal lymphangiogenesis | VEGFR-3 blockade cancels lymphangiogenesis. | 183 | |
| Chronic airway inflammation | VEGFR-3 blockade cancels lymphangiogenesis. | 184 | |
| LPS-induced peritonitis | VEGF-C and VEGF-D promote lymphangiogenesis in diaphragm. | 185 | |
| Ang 2 | Mouse corneal lymphangiogenesis | Ang 2 is upregulated in inflamed cornea, and Ang2 blockade inhibits inflammatory lymphangiogenesis. | 186 |
| Mouse corneal lymphangiogenesis | Ang 2 is expressed in lymphatic vessels and macrophages in inflamed cornea. Inflammatory lymphangiogenesis of cornea is suppressed in Ang2 knockout mice. Ang2 blockade inhibits LyEC proliferation and capillary tube formation. | 187 | |
| HGF | Canine primary LyEC, rat tail lymphedema | HGF promotes proliferation and migration of LyEC. Weekly HGF gene transfer improves lymphedema in vivo. | 188 |
| LT | CCL21 transgenic mouse, RAG knockout mouse defective in T and B cell | LT overexpression by CCL21 transgene promotes lymphangiogenesis in thyroid. T-cell depletion cancels this phenomenon. | 189 |
| LTα knockout mouse, LTα transgenic mouse | LTα gene deletion decreases LV. Ectopic LTα expression causes lymphangiogenesis in tertiary lymphoid organs. | 190 | |
| IL1β | Mouse corneal lymphangiogenesis | IL1β promotes lymphangiogenesis by upregulating expression of VEGF-A, VEGF-C, and VEGF-D. | 191 |
| IL7 | Breast cancer cell lines, subcutaneous injection of Matrigel and/or IL7 and/or breast cancer cell lines | IL7 promotes VEGF-D expression of cell lines in vitro and promotes lymphangiogenesis in vivo. | 192 |
| HECV cell line (originated from human umbilical cord), subcutaneous injection of Matrigel and/or IL7 and/or HECV cell | IL7 promotes expression of Prox1, LYVE-1, and podoplanin and proliferation, migration, and tubular formation of LyEC via upregulation of VEGF-D. | 193 | |
| IL8 | Human primary LyEC, IL8 transgenic mouse and Prox1-GFP mouse | IL8 promotes proliferation, migration, and tube formation of LyEC. IL8 overexpression promotes lymphangiogenesis in vivo. | 194 |
| IL17 | Cornea micro pocket assay, autoimmune ocular disease mouse | IL17 promotes proliferation of LyEC via upregulation of VEGF-D. Blockade of IL17 decreases corneal lymphangiogenesis. | 195 |
| IL20 | Human telomerase-transfected dermal LyEC | IL20 promotes proliferation, migration, and tubular formation of LyEC via PI3K and mTOR pathways. | 196 |
| Anti-lymphangiogenic factors | |||
| TGF-β | Human dermal lymphatic microvascular endothelial cells | TGF-β inhibits LyEC proliferation, cord formation, migration, expression of lymphatic markers (LYVE-1, Prox1), and lymphangiogenesis by VEGF-A/C via TGF-β type I receptor. | 197 |
| Mouse tail skin excision and lymphatic vessel ligation | TGF-β1 inhibition promotes lymphatic vessel regeneration. TGF-β1 inhibits LyEC proliferation and fibrosis. | 198 | |
| Biopsy specimens from limbs of secondary lymphedema patients and mouse tail skin excision | TGF-β1 positive cells increase 3-fold in human lymphedema specimens. TGF-β1 inhibition decreases fibrosis, increases lymphangiogenesis and lymphatic function. | 199 | |
| BMP2 | Zebrafish BMP2 transgenic model | BMP2 inhibits LyEC differentiation from cardinal veins via inhibition of Prox1 expression. | 200 |
| IFN-α, IFN-γ | LyEC isolated from pig thoracic duct | IFN-α or IFN-γ decreases LyEC proliferation and migration. Treatment with both IFN-α and IFN-γ promotes LyEC apoptosis. | 201 |
| Cervical LNs of T-cell–deprived mouse | T cells inhibit lymphangiogenesis in LNs by secreting IFN-γ. | 116 | |
| IL4, IL13 | Mouse LyEC isolated from LNs, human dermal LyEC, mouse asthma model | IL4 and IL13 inhibit expression of Prox1 and LYVE-1 and tube formation of LyEC. Blockade of IL4 and/or IL13 increases the density and function of lung LVs in asthma model. | 202 |
| IL27 | Human dermal lymphatic microvascular endothelial cells | IL27 inhibits LyEC proliferation and migration via STAT1/CXCL10, CXCL-11 axis. | 203 |
| Activin A | Subcutaneous injection of melanoma cell line to mouse | Activin A reduces lymphangiogenesis in melanoma model and inhibits sprouting of LyEC via phosphorylation of SMAD2. | 204 |
FGF-2, fibroblast growth factors-2; HGF, hepatocyte growth factor; HSV-1, herpes simplex virus 1; LN, lymph node; LPS, lipopolysaccharide; LT, lymphotoxin; LV, lymphatic vessel; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; STAT, signal transducer and activator of transcription; TGF, tumor growth factor.