VEGF Receptor 1-Expressing Macrophages Recruited from Bone Marrow Enhances Angiogenesis in Endometrial Tissues

Abstract

Angiogenesis is critical in maintenance of endometrial tissues. Here, we examined the role of VEGF receptor 1 (VEGFR1) signaling in angiogenesis and tissue growth in an endometriosis model. Endometrial fragments were implanted into the peritoneal wall of mice, and endometrial tissue growth and microvessel density (MVD) were determined. Endometrial fragments from wild-type (WT) mice grew slowly with increased angiogenesis determined by CD31 + MVD, peaking on Day 14. When tissues from WT mice were transplanted into VEGFR1 tyrosine kinase-knockout mice, implant growth and angiogenesis were suppressed on Day 14 compared with growth of WT implants in a WT host. The blood vessels in the implants were not derived from the host peritoneum. Immunostaining for VEGFR1 suggested that high numbers of VEGFR1 + cells such as macrophages were infiltrated into the endometrial tissues. When macrophages were deleted with Clophosome N, both endometrial tissue growth and angiogenesis were significantly suppressed. Bone marrow chimera experiments revealed that growth and angiogenesis in endometrial implants were promoted by host bone marrow-derived VEGFR1 + /CD11b + macrophages that accumulated in the implants, and secreted basic fibroblast growth factor (bFGF). A FGF receptor kinase inhibitor, PD173047 significantly reduced size of endometrial tissues and angiogenesis. VEGFR1 signaling in host-derived cells is crucial for growth and angiogenesis in endometrial tissue. Thus, VEGFR1 blockade is a potential treatment for endometriosis.

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

“…Using bone marrow chimeras they demonstrated that VEGFR1 + cells in lesions were bone marrow derived CD11b + macrophages (125). WT endometriosis mice were also treated with clophosome N which depleted phagocytic cells in the peritoneal cavity at the time of endometriosis induction, and demonstrated that growth and angiogenesis in lesions was reduced (125). A similar study using liposomal bisphosphonate to deplete phagocytic peritoneal populations also demonstrated reduced growth of endometriosis lesions in a rat model (138).…”

“…Although, peritoneal macrophages contribute to inflammation in endometriosis, it remains unknown whether they infiltrate endometriosis lesions and thus the role these cells play within the ectopic tissue is not known. Using bone marrow chimeras Sekiguchi et al demonstrated that CD11b + cells from the bone marrow infiltrate and accumulate in endometriosis lesions in a mouse model (125). These cells could represent a monocyte/macrophage population, although CD11b + cells could also constitute neutrophils, eosinophils and or certain subsets of dendritic cells (126).…”

“…Sekiguchi et al demonstrated that VEGFR1 knockout mice had smaller and less vascularized lesions than WT in a mouse model where sections of uterus were sutured onto the peritoneal wall. Using bone marrow chimeras they demonstrated that VEGFR1 + cells in lesions were bone marrow derived CD11b + macrophages (125). WT endometriosis mice were also treated with clophosome N which depleted phagocytic cells in the peritoneal cavity at the time of endometriosis induction, and demonstrated that growth and angiogenesis in lesions was reduced (125).…”

Large‐scale production, purification, and function of a tumor multi‐epitope vaccine: Peptibody with bFGF/VEGFA

“…Moreover, there exists a synergistic effect between bFGF and VEGFA to form new vessels through platelet-derived growth factor signal pathway [3]. It has been demonstrated that tumorigenesis will be withdrawn if the signal pathways of tumor angiogenesis are blockaded [4]. Thus, angiogenesis inhibition may be a viable treatment approach for the highly vascular tumor types, such as ovarian cancer, lung cancer and breast cancer [5][6][7].…”

Implication of VEGFR2 in endometriosis: A structural biological and genetic approach

“…Among these, a main angiogenic mediator that has attracted much attention is vascular endothelial growth factor (VEGF), which has been suggested to play an important role in the development of endometriosis in combination with its endothelial selective receptor, VEGFR2 (16), also known as kinase insert domain receptor (KDR) (17). VEGF proteins play specific roles in controlling the growth of new blood vessels, while VEGF receptor signal transduction mediates endothelial cell proliferation, migration, organization into functional vessels and the remodeling of the vessel network (18,19). VEGF is produced by endothelial cells, monocytes and fibroblasts in response to hypoxia, which is the major physiological signal for angiogenesis through the activation of its receptor, VEGFR2, which is a member of the tyrosine kinase superfamily (20).…”