Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation.

Abstract

OBJECTIVE:

One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation.

METHODS AND RESULTS:

Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate-dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts.

CONCLUSIONS:

Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.

• Authors: Kanako Hosono, Tatsunori Suzuki, Hideaki Tamaki, Hiroyuki Sakagami, Izumi Hayashi, Shuh Narumiya, Kari Alitalo, Masataka Majima
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 5 Pg. 1049-58 (May 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21311040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Glycoproteins
• Gp38 protein, mouse
• Membrane Glycoproteins
• Membrane Transport Proteins
• Ptger1 protein, mouse
• Ptger2 protein, mouse
• Ptger3 protein, mouse
• Ptger4 protein, mouse
• Pyrazoles
• Receptors, Prostaglandin E, EP1 Subtype
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP3 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Sulfonamides
• Vascular Endothelial Growth Factor C
• Vascular Endothelial Growth Factor D
• Xlkd1 protein, mouse
• vascular endothelial growth factor C, mouse
• Fibroblast Growth Factor 2
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Vascular Endothelial Growth Factor Receptor-3
• Intramolecular Oxidoreductases
• Prostaglandin-E Synthases
• Celecoxib
• Dinoprostone

Topics

• Animals
• Celecoxib
• Cells, Cultured
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dinoprostone (metabolism)
• Fibroblast Growth Factor 2 (administration & dosage)
• Fibroblasts (drug effects, metabolism)
• Glycoproteins (metabolism)
• Granulation Tissue (drug effects, metabolism, physiopathology)
• Injections, Subcutaneous
• Intramolecular Oxidoreductases (metabolism)
• Lymphangiogenesis (drug effects)
• Lymphatic Vessels (drug effects, metabolism, physiopathology)
• Macrophages (drug effects, metabolism)
• Male
• Membrane Glycoproteins (metabolism)
• Membrane Transport Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Prostaglandin-E Synthases
• Pyrazoles (pharmacology)
• Receptors, Prostaglandin E, EP1 Subtype (genetics, metabolism)
• Receptors, Prostaglandin E, EP2 Subtype (genetics, metabolism)
• Receptors, Prostaglandin E, EP3 Subtype (deficiency, genetics, metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Time Factors
• Vascular Endothelial Growth Factor C (metabolism)
• Vascular Endothelial Growth Factor D (metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (metabolism)