Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress

Abstract

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.

Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen‐glucose deprivation

“…Because VEGFR-2 activation can increase phosphorylation of Akt, which promotes neuronal survival (Hao & Rockwell 2013), we compared the Akt phosphorylation state after exposure of neurons to OGD followed by astrocyte conditioned media. As shown in Fig.…”

“…However, this study did not examine VEGF. We focused on astrocyte release of VEGF because astrocytes release VEGF under hypoxic conditions (Sinor et al 1998, Schmid-Brunclik et al 2008), sEH inhibitors can promote VEGF release in other tissue (Panigrahy et al 2013, Sander et al 2011, Xu et al 2013), and VEGF can exert pro-survival effects in neurons (Hao & Rockwell 2013, Sanchez et al 2010). Here, we found that administration of sEH inhibitors without exposure to OGD produced 25–33% increases in VEGF in the astrocyte medium.…”

“…Second, medium derived from astrocytes that are treated with sEH inhibitors after OGD augments the pro-survival phosphorylation of Akt in OGD-exposed neurons. We also determined whether this augmentation requires activation of neuronal VEGF receptor-2 (VEGFR2), the primary receptor mediating neuronal protection by VEGF (Hao & Rockwell 2013). Throughout the studies, two structurally distinct sEH inhibitors were used:…”

VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases

“…To name a few, it provides neuroprotection and prevents mitochondrial dysfunction and oxidative stress in hippocampal neurons (54). VEGF-mediated VEGFR2-AKT survival is critical to neuroprotection via hypoxic preconditioning in cerebellar granule neurons (55).…”

Increased levels of vascular endothelial growth factor in patients with major depressive disorder: A meta-analysis

“…For example, VEGF has been proven to promote neurogenesis in the hippocampus (Fournier and Duman, 2012), provide neuroprotection (Feng et al, 2011), effect responses to stress (Nowacka and Obuchowicz, 2013), influence synaptic transmission (McCloskey et al, 2005), and protect neurons from oxidative stress (Hao and Rockwell, 2013). Furthermore, in one study conducted on a post-mortem brain of a patient with schizophrenia, the authors reported a significantly lower VEGF mRNA expression localized in the post-mortem dorsolateral prefrontal cortex (Fulzele and Pillai, 2009).…”