Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress.
Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress.
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DOI：
10.1016/j.freeradbiomed.2013.05.036
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发表时间：
2013-10
影响因子：
7.4
通讯作者：
Rockwell, Patricia
中科院分区：
文献类型：
--
作者：
Hao, Tianfeng;Rockwell, Patricia
血管内皮生长因子VEGF（VEGF-A或VEGF 165）是一种有效的血管生成因子，其也通过激活其同源受体VEGFR-2来发出神经保护信号。在这种能力下，VEGF信号可以拯救神经元免于由应激刺激诱导的损伤，其中许多应激刺激引起氧化应激。然而，VEGFR-2在提供神经保护中的调节作用仍然难以捉摸。因此，我们研究了VEGFR-2抑制对经历营养应激的成熟海马神经元原代培养物的影响。我们发现，在营养应激下培养的神经元VEGF及其受体VEGFR-1，VEGFR-2和NP-1的表达增加，以及VEGFR-2磷酸化水平增加。这些神经元还表现出MEK/ERK 1/2和PI 3 K/Akt的促存活途径的激活增加，促凋亡BAD的磷酸化（失活）增强和抗凋亡蛋白Bcl-xL的水平更高，所有这些都通过外源性VEGF治疗增强并通过VEGFR-2抑制来阻断。VEGFR-2功能的阻断还引起细胞毒性，伴随着半胱天冬酶-3活化、血红素加氧酶-1（HO-1）诱导、氧化应激和线粒体膜电位（Δ Δ pHlm）崩溃。通过siRNA敲低VEGFR-2产生了类似的氧化还原变化和线粒体损伤模式。用VEGF、VEGF-B或抗氧化剂N-乙酰半胱氨酸（NAC）预处理及时地将SU 1498或siRNA处理的神经元从由VEGFR-2抑制诱导的线粒体功能障碍和氧化应激中拯救出来。这些发现表明，VEGF或VEGF-B可以通过替代VEGF受体的信号传导提供神经保护。总之，我们的研究结果表明，通过VEGFR-2的VEGF信号在保护应激海马神经元免受氧化损伤的损伤作用中起着关键的调节作用。这些发现也暗示VEGFR-1或NP-1作为代偿性受体，当VEGFR-2功能被阻断时介导神经保护。
Vascular endothelia growth factor VEGF (VEGF-A or VEGF165) is a potent angiogenic factor that also signals neuroprotection through activation of its cognate receptor VEGFR-2. In this capacity, VEGF signaling can rescue neurons from the damage induced by stressful stimuli many of which elicit oxidative stress. However, the regulatory role that VEGFR-2 plays in providing neuroprotection remains elusive. Therefore, we investigated the effects of VEGFR-2 inhibition on primary cultures of mature hippocampal neurons undergoing nutritional stress. We found that neurons cultured under nutritional stress had increased expression of VEGF and its receptors, VEGFR-1, VEGFR-2 and NP-1 as well as enhanced levels of VEGFR-2 phosphorylation. These neurons also showed increased activation of the prosurvival pathways for MEK/ERK1/2 and PI3K/Akt, enhanced phosphorylation (inactivation) of the pro-apoptotic BAD and higher levels of the anti-apoptotic protein Bcl-xL, all of which were augmented by treatments with exogenous VEGF and blocked by VEGFR-2 inhibition. The blockade of VEGFR-2 function also elicited a cytotoxicity that was accompanied by caspase-3 activation, induction of hemeoxygenase-1 (HO-1), oxidative stress and a collapse in the mitochondrial membrane potential (Δψlm). Knockdown of VEGFR-2 by siRNA generated a similar pattern of redox change and mitochondrial impairment. Pretreatments with VEGF, VEGF-B or the antioxidant N-acetyl-cysteine (NAC) rescued SU1498 or siRNA treated neurons from the mitochondrial dysfunction and oxidative stress induced by VEGFR-2 inhibition in a timely fashion. These findings suggested that VEGF or VEGF-B can provide neuroprotection by signaling through an alternate VEGF receptor. Together, our findings suggest that VEGF signaling through VEGFR-2 plays a critical regulatory role in protecting stressed hippocampal neurons from the damaging effects of an oxidative insult. These findings also implicate VEGFR-1 or NP-1 as compensatory receptors that mediate neuroprotection when VEGFR-2 function is blocked.
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发表时间：
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期刊：
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