Roles of Prostaglandin E2–EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation …

K Hosono, T Suzuki, H Tamaki… - … , and vascular biology, 2011 - Am Heart Assoc
K Hosono, T Suzuki, H Tamaki, H Sakagami, I Hayashi, S Narumiya, K Alitalo, M Majima
Arteriosclerosis, thrombosis, and vascular biology, 2011Am Heart Assoc
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 …
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.
Conclusion
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.
Am Heart Assoc