Kayisli Umit A, Basar Murat, Guzeloglu-Kayisli Ozlem, Semerci Nihan, Atkinson Helen C, Shapiro John, Summerfield Taryn, Huang S Joseph, Prelle Katja, Schatz Frederick, Lockwood Charles J
Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612;
Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University, Columbus, OH 43210;
Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5153-8. doi: 10.1073/pnas.1424814112. Epub 2015 Apr 6.
Molecular mechanisms responsible for abnormal endometrial vasculature in women receiving long-acting progestin-only contraceptives (LAPCs) are unknown. We hypothesize that LAPCs impair vascular smooth muscle cell (VSMC) and pericyte proliferation and migration producing thin-walled hyperdilated fragile microvessels prone to bleeding. Proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (αSMA) double-immunostaining assessed VSMC differentiation and proliferation in endometria from women before and after DepoProvera (Depo) treatment and from oophorectomized guinea pigs (OVX-GPs) treated with vehicle, estradiol (E2), medroxyprogesterone acetate (MPA), or E2+MPA. Whole-genome profiling, proliferation, and migration assays were performed on cultured VSMCs treated with MPA or etonogestrel (ETO). Endometrial vessels of Depo-administered women displayed reduced αSMA immunoreactivity and fewer PCNA (+) nuclei among αSMA (+) cells (P < 0.008). Microarray analysis of VSMCs identified several MPA- and ETO-altered transcripts regulated by STAT1 signaling (P < 2.22 × 10(-6)), including chemokine (C-C motif) ligand 2 (CCL2). Both MPA and ETO reduce VSMC proliferation and migration (P < 0.001). Recombinant CCL2 reversed this progestin-mediated inhibition, whereas a STAT1 inhibitor abolished the CCL2 effect. Similarly, the endometria of MPA treated OVX-GPs displayed decreased αSMA staining and fewer PCNA (+) nuclei in VSMC (P < 0.005). In conclusion, LAPCs promote abnormal endometrial vessel formation by inhibiting VSMC proliferation and migration.
接受长效单纯孕激素避孕药（LAPC）的女性子宫内膜血管异常的分子机制尚不清楚。我们推测，LAPC会损害血管平滑肌细胞（VSMC）和周细胞的增殖与迁移，从而产生易于出血的薄壁、高度扩张且脆弱的微血管。通过增殖细胞核抗原（PCNA）和α平滑肌肌动蛋白（αSMA）双重免疫染色，评估了接受醋酸甲羟孕酮（Depo）治疗前后女性子宫内膜以及接受载体、雌二醇（E2）、醋酸甲羟孕酮（MPA）或E2 + MPA治疗的去卵巢豚鼠（OVX - GP）子宫内膜中VSMC的分化和增殖情况。对用MPA或依托孕烯（ETO）处理的培养VSMC进行全基因组分析、增殖和迁移测定。接受Depo治疗的女性子宫内膜血管中，αSMA免疫反应性降低，αSMA（+）细胞中PCNA（+）细胞核数量减少（P < 0.008）。对VSMC进行微阵列分析发现，有几种受STAT1信号调节的转录本在MPA和ETO处理后发生了改变（P < 2.22×10⁻⁶），包括趋化因子（C - C基序）配体2（CCL2）。MPA和ETO均降低了VSMC的增殖和迁移能力（P < 0.001）。重组CCL2可逆转这种孕激素介导的抑制作用，而STAT1抑制剂则消除了CCL2的作用。同样，用MPA处理的OVX - GP子宫内膜中，VSMC的αSMA染色减少，PCNA（+）细胞核数量减少（P < 0.005）。总之，LAPC通过抑制VSMC的增殖和迁移促进子宫内膜血管异常形成。
