Roles of Prostaglandins in Facilitation of Angiogenesis <I>in vivo</I>

Abstract

Angiogenesis, the formation of new blood vessels from the pre-existent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatories (NSAIDs) are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Recent results obtained from prostaglandin (PG) receptor knockout mice indicate that host stromal PGE type receptor signaling is crucial in tumor-associated angiogenesis. Implanted tumor growth and tumor-associated angiogenesis were markedly suppressed in EP3 receptor knockout mice (EP3-/-), in comparison with their wild-type counterparts (WT). Tumor-associated angiogenesis in WT depends on vascular endothelial growth factor (VEGF). Major VEGF-expressing cells in stroma were CD3/Mac-1 double-negative fibroblasts, and that stromal VEGF expression was markedly reduced in EP3-/-. An EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT. The wound healing process was significantly delayed in EP3-/-. The bone marrow transplantation of EP3-/- bone marrow cells revealed that the recruitment of EP3-expressing bone marrow cells to the wound granulation tissues was critical to the healing of wounds. These demonstrate the significance of EP receptor signaling to the angiogenesis in vivo. Such signaling will be a good target for controlling angiogenesis in pathological conditions.