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.
Highlights
Www.nature.com/scientificreports disorganization of blood vessels, suggesting that VEGF receptor 1 (VEGFR1) is a negative regulator of angiogenesis during embryonic development
Accumulation of VEGFR1+ macrophages from the host bone marrow was the key driver of growth and angiogenesis in the endometrial implants
We recently reported that angiogenic responses in mice with hindlimb ischemia were enhanced by VEGFR1 signaling but not by VEGFR2 signaling[18], suggesting that the receptors responsible for signaling during ischemia and endometriosis were similar
Summary
Www.nature.com/scientificreports disorganization of blood vessels, suggesting that VEGFR1 is a negative regulator of angiogenesis during embryonic development. We recently showed that VEGFR1 signaling facilitates angiogenesis during recovery from ischemia and gastric ulcers[17,18]. We found that VEGF neutralizing antibody treatment reduced the growth of endometrial tissue and angiogenesis in a mouse transplantation model[24]. The implantation of endometrial tissues isolated from wild type (WT) mice to the peritoneal cavity in VEGFR1TK−/− mice showed reduced angiogenesis and growth of implants, suggesting that host VEGFR1 signaling is critical for the maintenance of implants[24]. It remains unknown how VEGFR1 signaling regulates angiogenesis and development of endometriosis. This study suggests that blocking VEGFR1 with antibodies or small molecule kinase inhibitors may become a promising option to the treatment of endometriosis
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