Preserved fertility despite erectile dysfunction in mice lacking the nitric oxide receptor
Preserved fertility despite erectile dysfunction in mice lacking the nitric oxide receptor
复制标题
尽管缺乏一氧化氮受体的小鼠存在勃起功能障碍，但仍保留了生育能力
DOI：
10.1113/jphysiol.2012.245555
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Friebe A.
中科院分区：
文献类型：
--
作者：
Groneberg D;Lies B;König P;Jäger R;Friebe A.
勃起功能障碍可能是由一氧化氮（NO）/cGMP介导的信号传导减少或无功能引起的。缺乏一氧化氮合酶的小鼠具有生育能力，而缺乏cGMP依赖性蛋白激酶I的小鼠则患有勃起功能障碍。为了澄清这一差异，我们对缺乏NO受体NO敏感性鸟苷酸环化酶（NO-GC）的雄性小鼠阴茎海绵体进行了研究，无论是在整体上还是在平滑肌细胞中。从NO供体以及从氮能神经元释放的NO未能放松来自缺乏NO-GC的小鼠的预先收缩的阴茎海绵体，无论是全局还是特异性地在平滑肌中;令我们惊讶的是，来自两个敲除系的雄性都是可育的。我们的数据表明，特异性地在平滑肌细胞中的NO受体的缺失废除NO诱导的阴茎海绵体松弛，但不导致infertiles.AbstractNitric oxide（NO）和cGMP已被证明是阴茎勃起的重要介质。勃起功能障碍可能是由于该级联中的信号转导减少或无功能。然而，现有数据存在一些不一致之处，因为缺乏一氧化氮合酶（内皮和神经元一氧化氮合酶，或两者兼而有之）的小鼠似乎具有生育能力，而缺乏cGMP依赖性蛋白激酶I（PKGI）的小鼠则患有勃起功能障碍。为了澄清这种差异，我们对缺乏NO受体NO-敏感鸟苷酸环化酶（NO-GC）的小鼠进行了研究。此外，我们产生了细胞特异性NO-GC敲除（KO）系，以研究NO在单个细胞类型中的功能。NO-GC在平滑肌或内皮细胞中特异性缺失（分别为SM-鸟苷酸环化酶敲除（SM-GCKO）和EC-GCKO），并将这些KO系与总敲除（GCKO）和野生型动物进行比较。我们研究了NO-GC的表达，NO诱导的阴茎海绵体平滑肌松弛及其产生后代的能力。在小鼠阴茎海绵体的平滑肌和内皮细胞中检测到NO-GC-阳性免疫染色，但在Cajal间质细胞中未检测到。在器官浴实验中，NO供体和氮能神经元释放的NO不能舒张GCKO小鼠阴茎海绵体预收缩。在SM-GCKO小鼠的阴茎海绵体中获得了类似的结果，而内皮细胞中NO-GC的缺失不影响舒张。在GCKO动物中缺乏NO诱导的舒张不能通过鸟苷3′，5 ′-环磷酸（cGMP）信号传导来补偿。令我们惊讶的是，GCKO雄性是有生育能力的，尽管它们生育后代的能力下降了。我们的数据表明，特异性地在平滑肌细胞中缺失NO-GC可以消除NO诱导的阴茎海绵体松弛，但不会导致不育。
Key points•Erectile dysfunction may result from reduced or non‐functional nitric oxide (NO)/cGMP‐mediated signalling. Mice lacking NO synthases are fertile whereas mice deficient in cGMP‐dependent protein kinase I suffer from erectile dysfunction.•To clarify this discrepancy we performed studies on the corpus cavernosum of male mice lacking the NO receptor NO‐sensitive guanylyl cyclase (NO‐GC) either globally or specifically in smooth muscle cells.•NO released from NO donors as well as from nitrergic neurons failed to relax precontracted corpus cavernosum from mice lacking NO‐GC either globally or specifically in smooth muscle; to our surprise, males from both knockout lines were fertile.•Our data show that deletion of the NO receptor specifically in smooth muscle cells abolishes NO‐induced corpus cavernosum relaxation but does not lead to infertility.AbstractNitric oxide (NO) and cGMP have been shown to be important mediators of penile erection. Erectile dysfunction may result from reduced or non‐functional signal transduction within this cascade. There is, however, some inconsistency in the available data as mice lacking NO synthases (endothelial and neuronal nitric oxide synthase, or both) appear to be fertile whereas mice deficient in cGMP‐dependent protein kinase I (PKGI) suffer from erectile dysfunction. To clarify this discrepancy we performed studies on mice lacking the NO receptor NO‐sensitive guanylyl cyclase (NO‐GC). In addition, we generated cell‐specific NO‐GC knockout (KO) lines to investigate the function of NO in individual cell types. NO‐GC was specifically deleted in smooth muscle or endothelial cells (SM‐guanylyl cyclase knockout (SM‐GCKO) and EC‐GCKO, respectively) and these KO lines were compared with total knockouts (GCKO) and wild‐type animals. We investigated expression of NO‐GC, NO‐induced relaxation of corpus cavernosum smooth muscle and their ability to generate offspring. NO‐GC‐positive immunostaining was detected in smooth muscle and endothelial cells of murine corpus cavernosum but not in interstitial cells of Cajal. NO released from NO donors as well as from nitrergic neurons failed to relax precontracted corpus cavernosum from GCKO mice in organ bath experiments. Similar results were obtained in corpus cavernosum from SM‐GCKO mice whereas deletion of NO‐GC in endothelial cells did not affect relaxation. The lack of NO‐induced relaxation in GCKO animals was not compensated for by guanosine 3′,5′‐cyclic monophosphate (cGMP) signalling. To our surprise, GCKO males were fertile although their ability to produce offspring was decreased. Our data show that deletion of NO‐GC specifically in smooth muscle cells abolishes NO‐induced corpus cavernosum relaxation but does not lead to infertility.
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DOI：
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DOI：
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发表时间：
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期刊：
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