Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
J Neurotrauma. 2012 Feb 10;29(3):528-38. doi: 10.1089/neu.2011.2036. Epub 2011 Dec 15.
Nitric oxide (NO) is an important regulator of vasodilation and angiogenesis in the central nervous system (CNS). Signaling initiated by the membrane receptor CD47 antagonizes vasodilation and angiogenesis by inhibiting synthesis of cyclic guanosine monophosphate (cGMP). We recently found that deletion of CD47 led to significant functional locomotor improvements, enhanced angiogenesis, and increased epicenter microvascular perfusion in mice after moderate contusive spinal cord injury (SCI). We tested the hypothesis that improving NO/cGMP signaling within the spinal cord immediately after injury would increase microvascular perfusion, angiogenesis, and functional recovery, with an acute, 7-day administration of the cGMP phosphodiesterase 5 (PDE5) inhibitor sildenafil. PDE5 expression is localized within spinal cord microvascular endothelial cells and smooth muscle cells. While PDE5 antagonism has been shown to increase angiogenesis in a rat embolic stroke model, sildenafil had no significant effect on angiogenesis at 7 days post-injury after murine contusive SCI. Sildenafil treatment increased cGMP concentrations within the spinal cord and improved epicenter microvascular perfusion. Basso Mouse Scale (BMS) and Treadscan analyses revealed that sildenafil treatment had no functional consequence on hindlimb locomotor recovery. These data support the hypothesis that acutely improving microvascular perfusion within the injury epicenter by itself is an insufficient strategy for improving functional deficits following contusive SCI.
一氧化氮（NO）是中枢神经系统（CNS）血管舒张和血管生成的重要调节剂。膜受体 CD47 引发的信号通路通过抑制环鸟苷酸单磷酸（cGMP）的合成来拮抗血管舒张和血管生成。我们最近发现，CD47 缺失可导致中度创伤性脊髓损伤（SCI）后小鼠的运动功能显著改善、血管生成增强和损伤中心微血管灌注增加。我们假设，在损伤后立即改善脊髓内的 NO/cGMP 信号，通过急性、7 天给予 cGMP 磷酸二酯酶 5（PDE5）抑制剂西地那非，会增加微血管灌注、血管生成和功能恢复。PDE5 表达定位于脊髓微血管内皮细胞和平滑肌细胞内。虽然 PDE5 拮抗作用已被证明可增加大鼠栓塞性中风模型中的血管生成，但在小鼠创伤性 SCI 后 7 天，西地那非对血管生成没有显著影响。西地那非治疗可增加脊髓内 cGMP 浓度并改善损伤中心微血管灌注。Basso 小鼠步态（BMS）和踏车扫描分析表明，西地那非治疗对后肢运动功能恢复没有功能影响。这些数据支持这样的假设，即在损伤中心内急性改善微血管灌注本身不足以改善创伤性 SCI 后的功能缺陷。
