Department of Obstetrics and Gynecology, Section of Maternal Fetal Medicine, The Warren Alpert Medical School of Brown University, Women & Infants' Hospital of Rhode Island, Providence, RI 02905, USA.
Reprod Sci. 2011 Feb;18(2):156-63. doi: 10.1177/1933719110382305. Epub 2010 Oct 19.
Fibrillar collagen in the cervical extracellular matrix (ECM) is the predominant component providing mechanical support. Cellular integrins contribute to structural integrity by cross-linking ECM components. We investigated the expression of collagen-binding integrins in the normal rat gestation and after treatment with mifepristone to determine whether integrin modulation is involved in changes in tissue resistance.
Cervical tissue was harvested from nonpregnant and timed pregnant Sprague-Dawley rats. Normal gestational expression was evaluated in nonpregnant and timed pregnant tissue on days 12, 16, 18, 20, 21 and 22. Progesterone inhibition was induced with 3 mg mifepristone administered on day 15. Primary rat cervical stromal (RCS) cell cultures were generated from nonpregnant rats using tissue explants. The effects of progesterone environment on RCS cells were evaluated in the presence and absence of various inhibitors. Protein expression and signaling pathways were evaluated by Western blot.
Integrin α2 (ITGA2) expression increased over gestation, peaking at the end of gestation (analysis of variance [ANOVA] P < .01). Integrin α11 (ITGA11) expression increased through mid-gestation, peaking on day 18 and decreasing through day 22 (ANOVA P < .001). Progesterone increased the expression of ITGA11 and phosphorylated focal adhesion kinase ([pFAK] P < .002). Mifepristone blocked these effects in vitro. Mifepristone increased ITGA2 and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) in vivo and in vitro. Mifepristone-induced upregulation of ITGA2 was abrogated by inhibition of ERK1/2.
Progesterone/progesterone withdrawal is involved in regulating the expression of collagen-binding integrins. These changes differ among the collagen-binding integrins. Mitogen-activated protein kinase (MAPK) signaling is involved in regulating some of these integrins.
细胞外基质（ECM）中的纤维胶原是提供机械支撑的主要成分。细胞整合素通过交联 ECM 成分有助于结构完整性。我们研究了正常大鼠妊娠期间和米非司酮治疗后胶原结合整合素的表达，以确定整合素调节是否参与组织阻力的变化。
从非妊娠和定时妊娠 Sprague-Dawley 大鼠中采集宫颈组织。在非妊娠和定时妊娠第 12、16、18、20、21 和 22 天评估正常妊娠表达。在第 15 天用 3mg 米非司酮诱导孕激素抑制。使用组织外植体从非妊娠大鼠中生成原代大鼠宫颈基质（RCS）细胞培养物。评估孕激素环境对 RCS 细胞的影响，同时存在和不存在各种抑制剂。通过 Western blot 评估蛋白表达和信号通路。
整合素α2（ITGA2）的表达随着妊娠而增加，在妊娠末期达到高峰（方差分析[ANOVA]P<.01）。整合素α11（ITGA11）的表达在中期增加，在第 18 天达到高峰，在第 22 天下降（ANOVA P<.001）。孕激素增加 ITGA11 和磷酸化粘着斑激酶（[pFAK]P<.002）的表达。米非司酮在体外阻断了这些作用。米非司酮在体内和体外增加 ITGA2 和磷酸化细胞外信号调节激酶 1 和 2（pERK1/2）的表达。ERK1/2 抑制阻断了米非司酮诱导的 ITGA2 上调。
孕激素/孕激素撤退参与调节胶原结合整合素的表达。这些变化在胶原结合整合素之间有所不同。丝裂原激活蛋白激酶（MAPK）信号参与调节其中一些整合素。
