(3)子宮筋腫における新しい細胞増殖シグナル伝達機構解析 : 子宮筋腫に対する子宮動脈塞栓術から分子標的療法へ(<特集>第59回シンポジウム1「子宮筋腫の発育制御とその管理」)

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Although uterine leiomyomas or fibroids are the most common gynecological benign tumor occurring in reproductive age women and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Uterine artery embolization(UAE) has been increasingly used as an alternative to hysterectomy, myomectomy and medical therapy for leiomyomata over the last decade. Most reports suggest that UAE is a well-tolerated and effective treatment for leiomyomata, although there have been no reports about changes of biological parameters after UAE. Numerous studies have shown that the growth of leiomyomas depends on the estrogen (E_2) and progesterone, but the other signaling pathway of uterine leiomyoma cell proliferation remains unknown. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Elevated blood pressure may cause smooth muscle cell injury and increase the risk of leiomyomata, in a process analogous to atherosclerotic changes in arterial smooth muscle cells. In this study, we investigated the signal transduction pathway of uterine leiomyoma cell proliferation according to the atherogenesis hypothesis of fibroid and we further analyzed the plasma level of vascular endothelial growth factor(VEGF) and the vascular impedance of uterine arteries before and after UAE. Epidemiological study showed that metabolic syndrome could be the risk factor for uterine leiomyoma. In vitro study using ELT-3 leiomyoma cell line showed that Angiotensin II(Ang II) significantly increased the ELT-3 cell number as effectively as E_2 treatment. Regarding the intracellular signaling pathway, the Ang II-induced cell proliferation pathway was AT_1R-, EGF receptor-, ERK-and PKC-dependent. The AT_1R blocker telmisartan effectively repressed Ang II-induced and E_2-induced cell proliferation. Hypoxia significantly increased the ELT-3 cell number. 2-methoxyestradiol(2ME2), hypoxia inducible factor(HIF) inhibitor, not only repressed the hypoxia-induced ELT-3 cell proliferation, but also repressed the ELT-3 cell proliferation under normoxic condition. Clinical study about the biological change after UAE showed that the level of VEGF increased and reached a peak value within 3 days after UAE and decreased thereafter and rose again on day 30. A significant inverse correlation was found between uterine artery PI and the level of VEGF on day 30. Ang II-induced leiomyoma cell proliferation may play a crucial role in the association of hypertension and uterine leiomyoma. Telmisartan is widely used clinically as antihypertensive medication, so this drug may be considered a potential tool in future uterine leiomyoma treatment strategy. The high level of VEGF secreted after UAE may induces angiogenesis and decreases the vascular impedance. It is possible that VEGF works to promote collateral formation and an increase of the blood supply to the fibroids after UAE. Anti-angiogenic therapy to block VEGF such as 2ME2 treatment may improve the treatment outcome of UAE.
社団法人日本産科婦人科学会の論文
2007-09-01

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