Regulation of vascular smooth muscle cell expression and function of matrix metalloproteinases is mediated by estrogen and progesterone exposure
Regulation of vascular smooth muscle cell expression and function of matrix metalloproteinases is mediated by estrogen and progesterone exposure
复制标题
DOI：
10.1016/j.jvs.2008.07.080
复制
发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Goldman, Mitchell H.
中科院分区：
文献类型：
--
作者：
Grandas, Oscar H.;Mountain, Deidra H.;Goldman, Mitchell H.
目的：据报道，接受激素替代疗法（HRT）的绝经后妇女在血管重建后有更多的不良结局，包括内膜增生增加和旁路移植失败。HRT可能影响导致内膜增生的途径。该途径的一个重要组成部分涉及基质金属蛋白酶（MMP），由于其降解细胞外基质组分的能力而与血管重塑有关。我们假设雌激素（Est）和孕激素（Prog）上调血管平滑肌细胞（VSMCs）的NIMP通路，从而增加MMP的活性和功能。将VSMC与Est（5 ng/mL）、Prog（50 ng/mL）、Est + Prog组合（Est/Prog）和/或多西环素（40 μ g/ml; Doxy）孵育。使用逆转录聚合酶链反应（RT-PCR）分析，我们以前已经表明膜型1-MW（MT 1-MMP）信使核糖核酸（mRNA）水平显着增加Est。在此，蛋白质印迹分析表明，MT 1-MMP和MMP-2蛋白水平，而不是MMP-2的组织抑制剂（TIMP-2），响应于Est和Est/Prog而增加（与对照相比P <0.05）。凝胶内酶谱显示Est和Est/Prog导致MMP-2活性增加（激素组，P <0.05 vs对照），激素组之间无显著差异。如使用改良的Boyden室测定所测量的，响应于Est，VSMC迁移增加了45 +/- 14%（P <0.05 vs对照）。强力霉素显著抑制MMP-2活性的基础和Est/Prog-stimulated增加（P <0.05 vs对照组; P <0.05 vs激素组），并部分阻断基底和垂体刺激的迁移（P < .05 vs对照组和Est）。结论：雌激素和孕酮通过增加MMP-2酶活性影响MMP途径，可能通过MT 1-MMP表达的上调而没有TIMP表达的相应增加。这种增加的胶原酶活性增加了VSMC的运动性及其通过IV型胶原晶格迁移的能力。MT 1-MMP的Est/Prog上调可能是HRT对血管介入治疗的不良影响。（J Vasc Surg 2009; 49：185-91.）
Objective: Postmenopausal women receiving hormone replacement therapy (HRT) have been reported to have more adverse outcomes after vascular reconstructions, including increased intimal hyperplasia development and bypass graft failure. HRT may be affecting the pathway contributing to intimal hyperplasia. An important component of this pathway involves matrix metalloproteinases (MMPs), implicated in vascular remodeling due to their ability to degrade components of the extracellular matrix. We hypothesize that estrogen (Est) and progesterone (Prog) upregulate the NIMP pathway in vascular smooth muscle cells (VSMCs) thereby increasing MMP activity and function.Methods and Results. VSMCs were incubated with Est (5 ng/mL), Prog (50 ng/mL), Est + Prog combination (Est/Prog), and/or doxycycline (40 mu g/ml; Doxy). Using reverse transcriptase polymerase chain reaction (RT- PCR) analysis we have previously shown membrane type 1-MW (MT1-MMP) messenger ribonucleic acid (mRNA) levels are significantly increased by Est. Here, Western blot analyses indicated MT1-MMP and MMP-2 protein levels, not tissue inhibitor of MMP-2 (TIMP-2), were increased in response to Est and Est/Prog (P < .05 vs control). In-gel zymography revealed that Est and Est/Prog resulted in increased MMP-2 activity (hormone groups, P < .05 vs control) with no significant difference among the hormone groups. VSMC migration was increased by 45 +/- 14% in response to Est (P < .05 vs control), as measured using a modified Boyden chamber assay. Doxycycline significantly inhibited basal and Est/Prog-stimulated increases in MMP-2 activity (P < .05 vs control; P < .05 vs hormone groups), and partially blocked basal and hormonally stimulated migration (P < .05 vs control and Est).Conclusion: Estrogen and progesterone affects the MMP pathway by increasing MMP-2 enzymatic activity, possibly via the upregulation of MT1-MMP expression without a corresponding increase in TIMP expression. This increased collagenase activity increases VSMC motility and their ability to migrate through a collagen type IV lattice. Est/Prog upregulation of MT1-MMP may contribute to the adverse effect of HRT on vascular interventions. (J Vasc Surg 2009; 49:185-91.)