Estrogen-induced CCN1 Is critical for establishment of endometriosis-like lesions in mice

Yuechao Zhao, Quanxi Li, Benita S. Katzenellenbogen, Lester F. Lau, Robert N. Taylor, Indrani C. Bagchi, Milan K. Bagchi

Research output: Contribution to journalArticle

Abstract

Endometriosis is a prevalent gynecological disorder in which endometrial tissue proliferates in extrauterine sites, such as the peritoneal cavity, eventually giving rise to painful, invasive lesions. Dysregulated estradiol (E) signaling has been implicated in this condition. However, the molecular mechanisms that operate downstream of E in the ectopic endometrial tissue are unknown. To investigate these mechanisms, we used a mouse model of endometriosis. Endometrial tissue from donor mice was surgically transplanted on the peritoneal surface of immunocompetent syngeneic recipient mice, leading to the establishment of cystic endometriosis-like lesions. Our studies revealed that treatment with E led to an approximately 3-fold increase in the lesion size within a week of transplantation. E also caused a concomitant stimulation in the expression of connective tissue growth factor/Cyr61/Nov (CCN1), a secreted cysteine-rich matricellular protein, in the lesions. Interestingly, CCN1 is highly expressed in human ectopic endometriotic lesions. To address its role in endometriosis, endometrial tissue from Ccn1-null donor mice was transplanted in wild-type recipient mice. The resulting ectopic lesions were reduced up to 75% in size compared with wild-type lesions due to diminished cell proliferation and cyst formation. Notably, loss of CCN1 also disrupted the development of vascular networks in the ectopic lesions and reduced the expression of several angiogenic factors, such as vascular endothelial growth factor-A and vascular endothelial growth factor-C. These results suggest that CCN1, acting downstream of E, critically controls cell proliferation and neovascularization, which support the growth and survival of endometriotic tissue at ectopic sites. Blockade of CCN1 signaling during the early stages of lesion establishment may provide a therapeutic avenue to control endometriosis.

Original languageEnglish (US)
Pages (from-to)1934-1947
Number of pages14
JournalMolecular Endocrinology
Volume28
Issue number12
DOIs
StatePublished - Jan 1 2014

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Endometriosis
Estrogens
Choristoma
Cell Proliferation
Vascular Endothelial Growth Factor C
Connective Tissue Growth Factor
Tissue Survival
Angiogenesis Inducing Agents
Peritoneal Cavity
Vascular Endothelial Growth Factor A
Cysteine
Blood Vessels
Cysts
Estradiol
Transplantation
Tissue Donors
Growth
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Estrogen-induced CCN1 Is critical for establishment of endometriosis-like lesions in mice. / Zhao, Yuechao; Li, Quanxi; Katzenellenbogen, Benita S.; Lau, Lester F.; Taylor, Robert N.; Bagchi, Indrani C.; Bagchi, Milan K.

In: Molecular Endocrinology, Vol. 28, No. 12, 01.01.2014, p. 1934-1947.

Research output: Contribution to journalArticle

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