雌二醇与二氢睾酮对血管内皮细胞增殖的影响和机制研究
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摘要
目的：1.研究二氢睾酮对不同来源的内皮细胞增殖和迁移的影响；
2.探讨二氢睾酮调控内皮细胞增殖的机制；
3.研究不同雌激素对雄激素诱导的内皮细胞增殖效应的影响。
方法：
1.分别用不同浓度二氢睾酮培养人主动脉内皮细胞和小鼠微血管内皮细胞24小时和48小时,MTS检测细胞增殖活力；分别将不同剂量雄激素受体(AR)siRNA或AR抑制剂Casodex与二氢睾酮10nM联合培养人主动脉内皮细胞48小时,分析二氢睾酮诱导的人主动脉内皮细胞增殖与雄激素受体的关系。
2.分别收集不同时间段LAPC-4(?)LNCaP细胞条件培养基(TCM)稀释成不同浓度培养小鼠微血管内皮细胞48小时,MTS法检测细胞增殖活力；用不同剂量二氢睾酮预处理LAPC-4和LNCaP细胞,48小时后收集TCM干预内皮细胞,MTS法检测细胞增殖活力；采用VEGFR抑制剂SU5416联合相应TCM培养内皮细胞24小时或48小时,用MTS方法检测细胞增殖活力；采用MDS法、实时定量PCR法分别检测相应TCM中、VEGF-A浓度和细胞VEGF mRNA的表达水平,分析VEGF/VEGFR通路在二氢睾酮诱导的小鼠微血管内皮细胞增殖中的作用。
3.细胞实验：单用或合用二氢睾酮、17a-雌二醇或17p-雌二醇培养人主动脉内皮细胞48小时,MTS法检测细胞活力；单用或合用二氢睾酮、17a-雌二醇或17β-雌二醇培养LAPC-4细胞48小时,收集TCM,用MDS法检测TCM中VEGF浓度,并用TCM干预小鼠微血管内皮细胞48小时,MTS法检测细胞活力。
动物实验：分别建立LAPC-4和LNCaP细胞异种移植的小鼠模型,将建模成功的小鼠随机分为安慰剂组、17a-雌二醇组和17β-雌二醇组,干预4周后处死小鼠收集移植组织,采用免疫组化法检测血管CD31的表达量,分析雌激素对微血管生成的影响。
结果：
1.二氢睾酮对不同来源内皮细胞增殖和迁移的影响：二氢睾酮1nM～50nM组人主动脉内皮细胞增殖活力较对照组增加,该增殖效应呈时间和剂量依赖性趋势。二氢睾酮对小鼠微血管内皮细胞增殖无明显影响。二氢睾酮10nM组HAECs迁移数较对照组增加(p<0.01)。
雄激素受体介导二氢睾酮诱导的人主动脉内皮细胞增殖：与二氢睾酮10nM相比,Casodex1μM～10μM联合二氢睾酮10nM干预后内皮细胞增殖活力显著降低(p<0.01)；二氢睾酮10nM可显著促进非特异性siRNA转染后人主动脉内皮细胞和对照组细胞的增殖活力(p<0.01),对AR siRNA转染后内皮细胞增殖无明显影响(p>0.05)。
2.二氢睾酮通过微环境促进小鼠微血管内皮细胞增殖：LAPC-4和LNCaP细胞TCM可时间和浓度依赖性地诱导小鼠微血管内皮细胞增殖；二氢睾酮O.1nM到50nM预处理后的TCM(DHT-TCM)较对照组TCM内皮细胞增殖活力明显增加(p<0.05)。
二氢睾酮诱导的小鼠微血管内皮细胞增殖与VEGF/VEGFR信号的相关性：收集时间点为24小时和48小时的LAPC-4细胞TCM中VEGF浓度分别是12.43ng/ml禾28ng/ml;但DHT-TCM和对照组TCM相比,各组间VEGF浓度差异无统计学意义(p>0.05)。SU541610μM可完全抑制相应TCM诱导的内皮细胞增殖(p<0.01)。
3.雌二醇联合二氢睾酮对人主动脉内皮细胞增殖的影响：17p-雌二醇联合二氢睾酮组人主动脉内皮细胞增殖活力较单用DHT10nnM组显著降低(p<0.05),而17a-雌二醇联合组与单用DHT10nM组对比细胞活力无明显差异(p>0.05)。
雌二醇联合二氢睾酮对小鼠微血管内皮细胞增殖的影响：单用或合用二氢睾酮、17a-雌二醇或17β-雌二醇对小鼠微血管内皮细胞增殖无明显直接影响。17a-雌二醇1μM或17β-雌二醇1μM可通过LAPC-4和LNCaP细胞抑制二氢睾酮10nM诱导的小鼠微血管内皮细胞增殖(p<0.01)。
雌二醇对小鼠微血管生成的影响：在LAPC-4异种移植小鼠中,17α-雌二醇组和17β-雌二醇组微血管数目较安慰剂组分别减少18%(p<0.05)和19%(p<0.05),在LNCaP前列腺癌小鼠中微血管数目可分别减少57.7%(p<0.01)和60.2%(p<0.01)。
结论：
1.二氢睾酮对不同来源的内皮细胞增殖具有差异性。
2.二氢睾酮可分别通过雄激素受体(AR)和微环境诱导内皮细胞增殖,微环境中VEGFR通路是二氢睾酮诱导的内皮增殖效应的重要通路。
3.雌二醇影响二氢睾酮诱导的内皮细胞增殖效应具有差异性。17β-雌二醇,而非17α-雌二醇可抑制雄激素诱导的主动脉内皮细胞增殖。而17β-雌二醇和17α-雌二醇均可通过周围细胞抑制雄激素诱导的小鼠微血管内皮细胞增殖和小鼠异种移植肿瘤内微血管形成。
Objective:1. To examine the direct effect of dihydrotestosterone (DHT) on cell proliferation and cell migration in different source of endothelial cells.
2. To explore the mechanism of DHT actions on endothelial cell proliferation.
3. To investigate the differential modulation of DHT action by estradiol.
Method:
1. Human arotic endothelial cells (HAECs) and murine microvascular endothelial cells (MECs) were treated with different doses of DHT for24hr and48hr, respectively. The number of viable cells was determined by MTS assay. To analyse the effect of AR on DHT-induced HAECs cell proliferation, HAECs were treated with DHT, AR siRNA or Casodex alone or in combination for48hr, MTS was used to test determine viable cells number.
2. TCMs collected from LAPC-4or LNCaP cells at24,48, and72hr of incubation were administrated to MECs at various concentrations and the number of viable MECs was determined at24or48hr of treatment. LAPC-4or LNCaP cells were treated with vehicle control or various doses of DHT for48hr, then TCMs were collected to treat MECs for48hr, MTS assay was used to test the viable cell number. To analyse the role of VEGF/VEGFR pathway in DHT-induced MECs cell proliferation, RT-PCR and MDS assay was used to test VEGF mRNA in cells and VEGF-A concentration in TCMs. Furthermore, MECs were treated with corresponding TCM and SU5416alone or in combination at doses indicated for48hours, and the viable cell number was determined.
3. Cell culture study:HAECs and MECs were treated with DHT,17a-estradiol or17β-estradiol alone or in combination at doses indicated for each experiment, the number of viable cells was determined by using MTS assay. To assess whether17a-estradiol and17β-estradiol can attenuate DHT-enhanced MEC cell growth through a paracrine mechanism by acting on tumor cells, MECs cells were treated with TCMs from LAPC-4cells treated with DHT,17a-estradiol or17β-estradiol alone or in combination for48hr, endothelial cell number was determined by MTS assay.
Animal study:Xenograft animal models with LAPC-4or LNCaP prostatic tumor were prepared, monitored and treated with a placebo,17a-estradiol or17β-estradiol pellet for4weeks, At the end of the4weeks, animals were euthanized and tumor tissues were collected, immunohistochemical analysis was applied to test CD31expression in tissues.
Result:
1. To explore the effect of DHT on cell proliferation in different source of endothelial cells, HAECs and MECs were treated with DHT at doses ranging from1nM to50nM in different time period. DHT produced a time-and dose-dependent cell proliferation in HAECs. While no significant effect was observed in MECs. To explore the effect of DHT on cell migration in HAECs, HAECs were pre-treated with DHT10nM, the migration cell number was increased (p<0.01)
To determine the role of AR in DHT-induced HAECs cell proliferation, AR siRNA and casodex was administrated to silence AR gene expression and block the combination of DHT and AR, respectively. The results showed that viable cell number was decreased significantly when treated with casodex (1μM～10μM) in combination with DHT10nM(p<0.01), or treated with DHT10nmol/L after siRNA transfection, the viable cell number was significantly decreased in cells transfected with AR siRNA (P<0.01), while no effect was observed in cells transfected with non-specific siRNA.
2. Tumor cell conditioned media (TCM) collected from LAPC-4or LNCaP cells produced a time-and concentration-dependent induction of cell growth in MECs. This TCM-induced cell growth in MECs was enhanced by the treatment of tumor cells with DHT. VEGF concentration in TCM collected at24hours and48hours was12.43ng/ml and28ng/ml, respectively. No significant difference was observed in the VEGF concentration between DHT-TCM and control-TCM. Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist.
3. In the model of DHT-induced HAECs cell proliferation, co-administration of17β-estradiol with DHT partly attenuated DHT-induced HAECs cell proliferation, but no effect was observed in17a-estradiol. Furthermore, co-administration of17a-estradiol or17P-estradiol with DHT in prostatic cells completely inhibited the DHT-enhancement effect, while treatment with DHT,17a-estradiol or17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of17a-estradiol or17β-estradiol in xenograft animals with LAPC-4or LNCaP tumor significantly decreased the micro vessel number in the tissues.
Conclusion:
1. Androgen produced different effect on cell proliferaion in different source of endothelial cells.
2. Androgen promotes endothelial cell proliferation via androgen receptor or microenvironment. VEGFR pathway in the miroenvironment is an important pathway involving in DHT-induced endothelial cell proliferation.
3. The androgen-induced endothelial cell growth is modulated by estrogen differentially.17β-estradiol, but not17a-estradiol, can inhibit the effect of DHT-induced HAECs cell proliferation. Both17a-estradiol and17β-estradiol is able to modulate DHT-induced MECs cell proliferation via tumor cells.
2.探讨二氢睾酮调控内皮细胞增殖的机制；
3.研究不同雌激素对雄激素诱导的内皮细胞增殖效应的影响。
方法：
1.分别用不同浓度二氢睾酮培养人主动脉内皮细胞和小鼠微血管内皮细胞24小时和48小时,MTS检测细胞增殖活力；分别将不同剂量雄激素受体(AR)siRNA或AR抑制剂Casodex与二氢睾酮10nM联合培养人主动脉内皮细胞48小时,分析二氢睾酮诱导的人主动脉内皮细胞增殖与雄激素受体的关系。
2.分别收集不同时间段LAPC-4(?)LNCaP细胞条件培养基(TCM)稀释成不同浓度培养小鼠微血管内皮细胞48小时,MTS法检测细胞增殖活力；用不同剂量二氢睾酮预处理LAPC-4和LNCaP细胞,48小时后收集TCM干预内皮细胞,MTS法检测细胞增殖活力；采用VEGFR抑制剂SU5416联合相应TCM培养内皮细胞24小时或48小时,用MTS方法检测细胞增殖活力；采用MDS法、实时定量PCR法分别检测相应TCM中、VEGF-A浓度和细胞VEGF mRNA的表达水平,分析VEGF/VEGFR通路在二氢睾酮诱导的小鼠微血管内皮细胞增殖中的作用。
3.细胞实验：单用或合用二氢睾酮、17a-雌二醇或17p-雌二醇培养人主动脉内皮细胞48小时,MTS法检测细胞活力；单用或合用二氢睾酮、17a-雌二醇或17β-雌二醇培养LAPC-4细胞48小时,收集TCM,用MDS法检测TCM中VEGF浓度,并用TCM干预小鼠微血管内皮细胞48小时,MTS法检测细胞活力。
动物实验：分别建立LAPC-4和LNCaP细胞异种移植的小鼠模型,将建模成功的小鼠随机分为安慰剂组、17a-雌二醇组和17β-雌二醇组,干预4周后处死小鼠收集移植组织,采用免疫组化法检测血管CD31的表达量,分析雌激素对微血管生成的影响。
结果：
1.二氢睾酮对不同来源内皮细胞增殖和迁移的影响：二氢睾酮1nM～50nM组人主动脉内皮细胞增殖活力较对照组增加,该增殖效应呈时间和剂量依赖性趋势。二氢睾酮对小鼠微血管内皮细胞增殖无明显影响。二氢睾酮10nM组HAECs迁移数较对照组增加(p<0.01)。
雄激素受体介导二氢睾酮诱导的人主动脉内皮细胞增殖：与二氢睾酮10nM相比,Casodex1μM～10μM联合二氢睾酮10nM干预后内皮细胞增殖活力显著降低(p<0.01)；二氢睾酮10nM可显著促进非特异性siRNA转染后人主动脉内皮细胞和对照组细胞的增殖活力(p<0.01),对AR siRNA转染后内皮细胞增殖无明显影响(p>0.05)。
2.二氢睾酮通过微环境促进小鼠微血管内皮细胞增殖：LAPC-4和LNCaP细胞TCM可时间和浓度依赖性地诱导小鼠微血管内皮细胞增殖；二氢睾酮O.1nM到50nM预处理后的TCM(DHT-TCM)较对照组TCM内皮细胞增殖活力明显增加(p<0.05)。
二氢睾酮诱导的小鼠微血管内皮细胞增殖与VEGF/VEGFR信号的相关性：收集时间点为24小时和48小时的LAPC-4细胞TCM中VEGF浓度分别是12.43ng/ml禾28ng/ml;但DHT-TCM和对照组TCM相比,各组间VEGF浓度差异无统计学意义(p>0.05)。SU541610μM可完全抑制相应TCM诱导的内皮细胞增殖(p<0.01)。
3.雌二醇联合二氢睾酮对人主动脉内皮细胞增殖的影响：17p-雌二醇联合二氢睾酮组人主动脉内皮细胞增殖活力较单用DHT10nnM组显著降低(p<0.05),而17a-雌二醇联合组与单用DHT10nM组对比细胞活力无明显差异(p>0.05)。
雌二醇联合二氢睾酮对小鼠微血管内皮细胞增殖的影响：单用或合用二氢睾酮、17a-雌二醇或17β-雌二醇对小鼠微血管内皮细胞增殖无明显直接影响。17a-雌二醇1μM或17β-雌二醇1μM可通过LAPC-4和LNCaP细胞抑制二氢睾酮10nM诱导的小鼠微血管内皮细胞增殖(p<0.01)。
雌二醇对小鼠微血管生成的影响：在LAPC-4异种移植小鼠中,17α-雌二醇组和17β-雌二醇组微血管数目较安慰剂组分别减少18%(p<0.05)和19%(p<0.05),在LNCaP前列腺癌小鼠中微血管数目可分别减少57.7%(p<0.01)和60.2%(p<0.01)。
结论：
1.二氢睾酮对不同来源的内皮细胞增殖具有差异性。
2.二氢睾酮可分别通过雄激素受体(AR)和微环境诱导内皮细胞增殖,微环境中VEGFR通路是二氢睾酮诱导的内皮增殖效应的重要通路。
3.雌二醇影响二氢睾酮诱导的内皮细胞增殖效应具有差异性。17β-雌二醇,而非17α-雌二醇可抑制雄激素诱导的主动脉内皮细胞增殖。而17β-雌二醇和17α-雌二醇均可通过周围细胞抑制雄激素诱导的小鼠微血管内皮细胞增殖和小鼠异种移植肿瘤内微血管形成。
Objective:1. To examine the direct effect of dihydrotestosterone (DHT) on cell proliferation and cell migration in different source of endothelial cells.
2. To explore the mechanism of DHT actions on endothelial cell proliferation.
3. To investigate the differential modulation of DHT action by estradiol.
Method:
1. Human arotic endothelial cells (HAECs) and murine microvascular endothelial cells (MECs) were treated with different doses of DHT for24hr and48hr, respectively. The number of viable cells was determined by MTS assay. To analyse the effect of AR on DHT-induced HAECs cell proliferation, HAECs were treated with DHT, AR siRNA or Casodex alone or in combination for48hr, MTS was used to test determine viable cells number.
2. TCMs collected from LAPC-4or LNCaP cells at24,48, and72hr of incubation were administrated to MECs at various concentrations and the number of viable MECs was determined at24or48hr of treatment. LAPC-4or LNCaP cells were treated with vehicle control or various doses of DHT for48hr, then TCMs were collected to treat MECs for48hr, MTS assay was used to test the viable cell number. To analyse the role of VEGF/VEGFR pathway in DHT-induced MECs cell proliferation, RT-PCR and MDS assay was used to test VEGF mRNA in cells and VEGF-A concentration in TCMs. Furthermore, MECs were treated with corresponding TCM and SU5416alone or in combination at doses indicated for48hours, and the viable cell number was determined.
3. Cell culture study:HAECs and MECs were treated with DHT,17a-estradiol or17β-estradiol alone or in combination at doses indicated for each experiment, the number of viable cells was determined by using MTS assay. To assess whether17a-estradiol and17β-estradiol can attenuate DHT-enhanced MEC cell growth through a paracrine mechanism by acting on tumor cells, MECs cells were treated with TCMs from LAPC-4cells treated with DHT,17a-estradiol or17β-estradiol alone or in combination for48hr, endothelial cell number was determined by MTS assay.
Animal study:Xenograft animal models with LAPC-4or LNCaP prostatic tumor were prepared, monitored and treated with a placebo,17a-estradiol or17β-estradiol pellet for4weeks, At the end of the4weeks, animals were euthanized and tumor tissues were collected, immunohistochemical analysis was applied to test CD31expression in tissues.
Result:
1. To explore the effect of DHT on cell proliferation in different source of endothelial cells, HAECs and MECs were treated with DHT at doses ranging from1nM to50nM in different time period. DHT produced a time-and dose-dependent cell proliferation in HAECs. While no significant effect was observed in MECs. To explore the effect of DHT on cell migration in HAECs, HAECs were pre-treated with DHT10nM, the migration cell number was increased (p<0.01)
To determine the role of AR in DHT-induced HAECs cell proliferation, AR siRNA and casodex was administrated to silence AR gene expression and block the combination of DHT and AR, respectively. The results showed that viable cell number was decreased significantly when treated with casodex (1μM～10μM) in combination with DHT10nM(p<0.01), or treated with DHT10nmol/L after siRNA transfection, the viable cell number was significantly decreased in cells transfected with AR siRNA (P<0.01), while no effect was observed in cells transfected with non-specific siRNA.
2. Tumor cell conditioned media (TCM) collected from LAPC-4or LNCaP cells produced a time-and concentration-dependent induction of cell growth in MECs. This TCM-induced cell growth in MECs was enhanced by the treatment of tumor cells with DHT. VEGF concentration in TCM collected at24hours and48hours was12.43ng/ml and28ng/ml, respectively. No significant difference was observed in the VEGF concentration between DHT-TCM and control-TCM. Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist.
3. In the model of DHT-induced HAECs cell proliferation, co-administration of17β-estradiol with DHT partly attenuated DHT-induced HAECs cell proliferation, but no effect was observed in17a-estradiol. Furthermore, co-administration of17a-estradiol or17P-estradiol with DHT in prostatic cells completely inhibited the DHT-enhancement effect, while treatment with DHT,17a-estradiol or17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of17a-estradiol or17β-estradiol in xenograft animals with LAPC-4or LNCaP tumor significantly decreased the micro vessel number in the tissues.
Conclusion:
1. Androgen produced different effect on cell proliferaion in different source of endothelial cells.
2. Androgen promotes endothelial cell proliferation via androgen receptor or microenvironment. VEGFR pathway in the miroenvironment is an important pathway involving in DHT-induced endothelial cell proliferation.
3. The androgen-induced endothelial cell growth is modulated by estrogen differentially.17β-estradiol, but not17a-estradiol, can inhibit the effect of DHT-induced HAECs cell proliferation. Both17a-estradiol and17β-estradiol is able to modulate DHT-induced MECs cell proliferation via tumor cells.
引文
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