综述|胰岛素样生长因子1在脑小血管病诊治中研究进展

1IGF-1及其信号系统

IGF-1主要由肝细胞产生并释放至血液，在全身各组织中发挥作用。IGF-1外周血浓度在青春期时达到高峰，约为400 ng/mL。此后，随着年龄的增长，IGF-1浓度逐渐下降，到75岁时大约只有100 ng/mL[7]。外周的IGF-1可通过血脑屏障（blood-brain barrier，BBB）进入脑脊液及脑实质。尽管如此，脑细胞局部自分泌或旁分泌产生的IGF-1仍被认为是大脑中IGF-1的主要来源，并且是在循环IGF-1水平较低时维持脑内浓度的一种内稳态机制[7]。MULLER等[8]研究显示，小鼠脑中局部产生的IGF-1并不足以代偿其外周血中随年龄增长而减少的IGF-1，而且这种衰老导致的IGF-1水平下降与认知功能障碍的发生相关。

IGF-1与细胞表面的IGF-1受体（insulin growth factor-1 receptor，IGF-1R）结合从而发挥其生物学作用。IGF-1R具有酪氨酸激酶活性，当IGF-1与其结合后，能磷酸化胰岛素受体底物（insulin receptor substrate, IRS）。磷酸化的IRS作为细胞内信号蛋白的停靠位点，可进一步激活磷脂酰肌醇3激酶（phosphatidylinositol 3-kinase，PI3K）/丝氨酸苏氨酸激酶（serine-threonine kinase，AKT）通路以及丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）通路。这两条信号通路的激活，会进一步调控下游众多的效应因子，实现复杂而多样的生物学作用。例如，磷酸化的AKT可通过调节哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR），增强蛋白质合成、核糖体发育和抑制促凋亡蛋白BAD的表达[9]。此外，活化的AKT还阻止了促凋亡FOXO基因的转录，从而促进海马神经元存活[10]。IGF-1可作用于神经元、星形胶质细胞和少突胶质细胞，通过减少细胞凋亡和促进细胞分化成熟在中枢神经系统发育过程中发挥着重要作用[11]。在脑血管损伤时，IGF-1也对不同的中枢细胞发挥着保护作用。神经元在缺血损伤时会发生兴奋性毒性死亡。研究表明，IGF-1可通过激活PI3K/AKT/mTOR通路保护海马神经元免受NMDA诱导兴奋性毒性损伤[12]。在脑出血小鼠中，IGF-1可通过TLR4/NF-κB途径改变小胶质细胞极化，减轻脑出血后的炎症反应[13]。IGF-1干预星形胶质细胞可以防止其发生缺血相关功能障碍，包括氧化应激和谷氨酸稳态破坏[14]。尽管IGF-1已被证明具有一定的保护作用，但其在不同的中枢神经细胞中的具体信号途径尚不十分明确。

2IGF-1用于预测卒中发生及预后的价值

目前关于IGF-1及脑血管病的临床研究主要集中于缺血性卒中，对于出血性卒中的研究仍较少。Framingham前瞻性队列研究显示，循环IGF-1基线水平处于最低的四分位或五分位的人群发生缺血性卒中的风险将增加2倍以上[15]。但是，KAPLAN等[16]研究发现IGF-1的水平与缺血性卒中的发生率无关。造成这种差异的原因目前尚不清楚，但值得我们注意的是，Framingham队列研究是一项前瞻性研究，患者在卒中前入组并采集血液样本用于IGF-1测定，而另一项研究则是量化了缺血性卒中发生后的IGF-1水平，这可能更多体现的是机体对缺血损伤的一种反应。DE SMEDT等[17]观察到，外周血高水平IGF-1（>75 ng/mL）的患者在起病3 d后神经缺损症状逐渐改善而且3个月的生存率较低水平组明显增加。一项研究对354例缺血性卒中患者进行了2年的跟踪随访发现，血清IGF-1的水平与3个月时的预后相关，而与长期（2年）预后未见明显相关性[18]。

然而，以上的临床研究均未对缺血性卒中进行具体分型。因此，由小血管病变引起的卒中与外周血IGF-1水平之间的关系尚不明确。最近的一项研究发现，CSVD伴认知功能障碍者的血清IGF-1水平较认知正常者的显著降低，这提示IGF-1可能在CSVD发展过程中发挥着重要的作用，但其具体的作用途径尚不清楚[19]。

3IGF-1对CSVD的潜在保护作用

3.1 改善内皮细胞功能障碍 内皮细胞是BBB和神经血管单元（neurovascular unit，NVU）的重要组成部分。内皮功能障碍主要表现为内皮细胞产生的有助于血管扩张和收缩物质失衡。血管内皮剪切应力增加可以直接激活内皮细胞中的内皮一氧化氮合酶（endothelial NO synthase，eNOS），促进一氧化氮（NO）释放[20]。内皮细胞产生的NO既可以使血管平滑肌松弛和小动脉扩张，从而调节局部脑血流量，还可通过抑制血管平滑肌细胞的增殖和纤维化来防止小动脉硬化，从而阻止脑白质病变和腔隙的发生发展。CSVD动物模型和患者的脑脊液中eNOS的含量降低，提示存在内皮功能障碍[21]。此外，CSVD的危险因素，如高龄和高血压等，会提高活性氧（reactive oxygen species，ROS）水平，驱动eNOS产生破坏性的超氧阴离子，进而进一步降低NO的生物利用度，引起血管舒张功能障碍，最终导致CSVD的发展[22]。

多项研究表明，IGF-1缺乏的动物模型通常表现出ROS产生增加和NO生物利用度降低等血管老化特征[23-24 ]。TARANTINI等[25]发现，循环IGF-1缺乏会加剧高血压诱导的血管氧化应激和破坏微血管结构，促进脑微出血的发生。外源性给予老龄大鼠IGF-1可上调内皮细胞中eNOS水平，提高NO的生物利用度[26]。此外，体外研究显示IGF-1可通过诱导内皮细胞增殖、迁移以及管形成等方面，从而调控血管新生[27]。在脑损伤模型小鼠中，外源性注射IGF-1可通过缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）/血管内皮生长因子（vascular endothelial growth factor，VEGF）依赖途径诱导脑微血管内皮细胞增殖，从而提高病灶周围血管密度[28-29 ]。

3.2 维持疾病状态下BBB的完整性 BBB主要由内皮细胞、内皮细胞之间的紧密连接（tight junctions，TJs）蛋白、基底膜、星形胶质细胞足突和周细胞组成，严格调节着大脑和血液之间的物质交换[30]。BBB破坏导致血液及血浆中其他成分外渗，造成血管周围间隙扩大、脑微出血和白质病变等。此外，这种损伤还可能增加细胞间质液体量，使小动脉壁增厚和变硬，进而使小动脉舒张受限，影响氧气及营养物质的运输[1]。研究显示CSVD患者BBB通透性增加，并与CSVD的总体负荷和认知功能下降的速度呈正相关[31]。

IGF-1R在构成血脑屏障的细胞上大量表达,体外实验显示TJs蛋白的表达受到IGF-1的调控[32]。既往研究表明，特异性敲除内皮细胞上的IGF-1R并不会导致BBB破坏[33]。但是TOTH等在IGF-1基因敲除鼠中发现，尽管在正常状态下外周血IGF-1缺乏不会导致BBB破坏，但在高血压背景下却会加剧BBB破坏[34]。同样，最近的一项研究观察到，在Apoe基因敲除小鼠中，内皮细胞特异性IGF1R信号通路中断会显著下调TJs蛋白表达，内皮通透性显著增加，表明IGF-1在维持内皮屏障功能方面起着重要作用[35]。

3.3 调节NVU功能 脑神经元、星形胶质细胞、脑小动脉内皮细胞和平滑肌细胞的相互协同作用调控NVU的功能。CSVD中小血管损伤使血管舒张储备下降，导致NVU功能下降，脑血流量不能满足大脑活跃区域氧气和能量的需求，并阻碍有毒代谢产物的清除，从而导致认知功能障碍的发生[36]。如前所述，IGF-1缺乏使脑微血管内皮细胞功能受损，NO生物利用度降低，血管舒张功能障碍，导致NVU损伤。除此以外，在IGF-1基因敲除小鼠中研究发现，IGF-1缺乏会使其星形胶质细胞上代谢型谷氨酸受体敏感性降低，导致钙内流减少，血管舒张物质生成不足，NVU自动调节功能受损，从而出现认知功能减退[37]。TARANTINI等[38]特异性敲除内皮细胞的IGF-1R也会损害小鼠NVU反应，出现衰老表型。最近，一项纳入31名中青年（18~40岁）和32名老年人（>60岁）的横断面研究显示，与年龄相关的外周血IGF-1水平下降与老年人NUC反应受损相关[39]。这些发现为IGF-1调节大脑中的NVU反应提供了强有力的证据。

3.4 改善CSVD脑白质病变 脑白质高信号（white matter hyperintensity，WMH）是CSVD患者磁共振上的显著特征之一。WMH病理改变主要是由于少突胶质细胞数量减少、脱髓鞘和轴突损伤引起。目前，脑灌注不足和BBB的破坏被认为是CSVD患者白质损伤的主要原因。研究发现脑血流量减少会引起少突胶质细胞发生缺血改变，从而损害髓鞘形成和修复[40]。此外，BBB的损伤导致有害毒素和免疫细胞进入大脑从而造成白质损伤。WARDLAW等[1]发现血浆中的纤维蛋白原通过受损的BBB泄漏入脑会阻碍少突胶质前体细胞分化成熟，从而抑制髓鞘的修复。IGF-1在正常大脑发育过程中可以促进少突胶质细胞增殖、分化及髓鞘形成。体外研究证明，IGF-1可以保护少突胶质细胞免受生长因子缺乏、TNFα介导的细胞毒性和兴奋性毒性的损害[41-43 ]。外源性给予IGF-1可以促进围产期缺血缺氧大鼠的髓鞘形成，改善其神经功能[44]。在慢性脱髓鞘大鼠模型中，IGF-1也被证明可以提高老年大鼠的髓鞘修复能力[45]。然而，目前IGF-1改善脑白质病变的研究大多数是在发育的大脑中发现，对于CSVD所致的脑白质病变，特别是在高龄、有血管危险因素等背景下，IGF-1对白质病变的保护作用仍有待进一步考究。

3.5 改善神经炎症反应 越来越多的研究表明炎症反应在CSVD发生发展过程中发挥着重要作用。在自发性高血压大鼠CSVD模型中，许多研究都报告小胶质细胞激活及内皮细胞周围出现T细胞浸润[46-47 ]。最近，有研究者提出慢性高血压和高龄会导致机体处于慢性、无菌、低级别炎症状态。这种由于细胞衰老所引起的慢性炎症反应会产生多种炎症介质来诱导全身和血管炎症，从而促进CSVD的进展[48]。研究发现，IGF-1可以改变小胶质细胞的激活状态，促进小胶质细胞向M2抗炎表型转变[13]。在缺血或出血性卒中后，外源性给予IGF-1可改善炎症反应从而减轻脑损伤[13, 49]。同时，小胶质细胞也是大脑局部IGF-1的主要来源。体内研究显示，小胶质细胞在急性缺血损伤后代偿性增殖，使内源性IGF-1分泌增多，从而减少神经元死亡和减轻炎症反应[50]。最近，FALOMIR-LOCKHART等[51]通过侧脑室注射IGF-1来抑制衰老引起的神经炎症反应，改善老年大鼠的运动功能。在LPS诱导的慢性神经炎症中，小胶质细胞产生IGF-1减少，从而导致神经变性[52]。这些结果表明，IGF-1可能通过改变小胶质细胞的表型从而减轻损伤后的炎症反应，今后需要在不同的环境背景下进一步证实。

4展望

IGF-1是健康大脑发育和神经元损伤后的重要保护因子。现有的证据显示IGF-1对CSVD发生发展过程中的多个病理过程都具有潜在保护作用，但具体作用途径及机制需进一步深入研究。另外，年龄相关的外周血IGF-1浓度改变与老年人CSVD发生率及严重程度的具体关系如何，IGF-1是否可以应用于CSVD的治疗以及其对CSVD病变的改善程度和具体机制，均有待进一步探讨。

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Research progress on insulin growth factor-1 in the diagnosis and treatment of cerebral small vessel disease

XU Xiangming FAN Yuhua

Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University

Abstract:Cerebral small vessel disease is the most significant risk factor for cognitive impairment in the elderly and is associated with gait disorders and mood disorders. The pathogenesis of cerebral small vessel disease is unclear. Thus, there is a lack of specific treatment. Insulin-like growth factor 1 is involved in embryonic development and neurogenesis and has a rule in normal growth and development. During the occurrence and development of cerebral small vessel disease, current studies suggest that IGF-1 plays a protective role by improving endothelial function, protecting blood-brain barrier integrity, regulating neurovascular unit function, improving cerebral white matter lesions and reducing neuroinflammation. In this paper, we summarize the current status of IGF-1 research in the occurrence and development of cerebral small vessel disease, propose the importance of further IGF-1-related research in cerebral small vessel disease, and provide a new direction for the diagnosis and treatment of cerebral small vessel disease.

Keywords:Insulin growth factor-1；Cerebral small vessel disease；Endothelial dysfunction；Blood-brain barrier；Neurovascular unit；Cerebral white matter lesions；Neuroinflammation

声明：本文作者享有本文著作权，《中国神经精神疾病杂志》专有本文出版权和信息网络传播权,转载请注明作者与出处。部分图转自网络。

初审：李立

审核：邢世会

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