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Endometriosis, a steroid hormone–dependent disease characterized by aberrant activation of estrogen receptor signaling and progesterone resistance, remains intractable because of the complexity of the pathways underlying its manifestation. We previously showed that eutopic endometria of women with endometriosis exhibit lower expression of Krüppel-like factor 9 (KLF9), a progesterone receptor coregulator in the uterus, relative to that of women without disease. Here we examined whether loss of endometrial KLF9 expression causes ectopic lesion establishment using syngeneic wild-type (WT) mice as recipients of endometrial fragments from WT and Klf9 null donors. We found significantly higher incidence of ectopic lesions with Klf9 null than WT endometria 8 weeks after tissue injection into the intraperitoneal cavity. The increased incidence of lesion establishment with Klf9 null endometria was associated with a higher expression ratio of estrogen receptor 2 isoform relative to that of estrogen receptor 1 and attenuated progesterone receptor levels in endometriotic stromal cells. PCR array analyses of Notch and Hedgehog signaling components in ectopic lesions demonstrated up-regulated expression of select genes (Jag 2, Shh, Gli1, and Stil 1) in Klf9 null lesions relative to that in WT lesions. Immunohistochemical analyses showed increased levels of Notch intracellular domain and Sonic Hedgehog proteins in Klf9 null lesions relative to that in WT lesions, confirming pathway activation. WT recipients with Klf9 null lesions displayed lower systemic levels of TNFα and IL-6 and higher soluble TNF receptor 1 than corresponding recipients with WT lesions. Our results suggest that endometrial KLF9 deficiency promotes endometriotic lesion establishment by the coincident deregulation of Notch-, Hedgehog-, and steroid receptor–regulated pathways.

endocrinology

Krüppel-Like Factor 9 Deficiency in Uterine Endometrial Cells Promotes Ectopic Lesion Establishment Associated With Activated Notch and Hedgehog Signaling in a Mouse Model of Endometriosis