Estrogen-induced CCN1 is critical for establishment of endometriosis-like lesions in mice.
Estrogen-induced CCN1 is critical for establishment of endometriosis-like lesions in mice.
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DOI：
10.1210/me.2014-1080
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发表时间：
2014-10
影响因子：
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通讯作者：
Yuechao Zhao;Quanxi Li;B. Katzenellenbogen;L. Lau;Robert N. Taylor;I. Bagchi;M. Bagchi
中科院分区：
文献类型：
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作者：
Yuechao Zhao;Quanxi Li;B. Katzenellenbogen;L. Lau;Robert N. Taylor;I. Bagchi;M. Bagchi
子宫内膜异位症是一种常见的妇科疾病，其中子宫内膜组织在子宫外部位（如腹膜腔）增殖，最终引起疼痛的侵袭性病变。雌二醇（E）信号转导失调与这种情况有关。然而，异位子宫内膜组织中E下游的分子机制尚不清楚。为了研究这些机制，我们使用了子宫内膜异位症的小鼠模型。将来自供体小鼠的子宫内膜组织手术移植到免疫活性的同系受体小鼠的腹膜表面，导致囊性子宫内膜样病变的建立。我们的研究表明，用E治疗导致移植后一周内病变大小增加约3倍。E还引起结缔组织生长因子/Cyr 61/Nov（CCN 1），一种分泌的富含半胱氨酸的基质细胞蛋白，在病变中的表达的伴随刺激。有趣的是，CCN 1在人类异位增生性病变中高度表达。为了解决其在子宫内膜异位症中的作用，将来自Ccn 1缺失供体小鼠的子宫内膜组织移植到野生型受体小鼠中。与野生型病变相比，由于细胞增殖和囊肿形成减少，所产生的异位病变的大小减少了75%。值得注意的是，CCN 1的缺失也破坏了异位病变中血管网络的发育，并减少了几种血管生成因子的表达，如血管内皮生长因子-A和血管内皮生长因子-C。这些结果表明，CCN 1，作用于下游的E，关键控制细胞增殖和新血管形成，支持异位部位的增生组织的生长和存活。在病变建立的早期阶段阻断CCN 1信号可能提供控制子宫内膜异位症的治疗途径。
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.