The Janus Face of VEGF in Stroke

Geiseler, Samuel J.; Morland, Cecilie

doi:10.3390/ijms19051362

Cited by 140 publications

(133 citation statements)

References 182 publications

(217 reference statements)

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“…The VEGF-A/vascular endothelial growth factor receptor (VEGFR)-2 signaling pathway is essential for recovery from cerebral damage after ischemic stroke [10,11]. VEGFs likely have multifaceted actions in stroke prevention and therapy [12]. Despite the potential adverse effects of VEGFs (e.g., vascular permeability and brain edema), the VEGF-A/VEGFR-2 signaling pathway has been used for acute or chronic treatment of stroke [9].…”

Section: Introductionmentioning

confidence: 99%

CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation

Kim

Lee

Zhang

et al. 2020

J Neuroinflammation

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Background: Ischemic stroke is a main cause of mortality. Blood-brain barrier (BBB) breakdown appears to play a critical role in inflammation in patients with ischemic stroke and acceleration of brain injury. The BBB has a protective function and is composed of endothelial cells, pericytes, and astrocytes. In ischemic stroke treatments, regulation of vascular endothelial growth factor (VEGF)-A and vascular endothelial growth factor receptor (VEGFR)-2 is a crucial target despite adverse effects. Our previous study found that loss of C-type lectin family 14 member A (CLEC14A) activated VEGF-A/VEGFR-2 signaling in developmental and tumoral angiogenesis. Here, we evaluate the effects of BBB impairment caused by CLEC14A deficiency in ischemia-reperfusion injury. Methods: In vitro fluorescein isothiocyanate (FITC)-dextran permeability, transendothelial electrical resistance (TEER) assay, and immunostaining were used to evaluate endothelial integrity. BBB permeability was assessed using Evans blue dye and FITC-dextran injection in Clec14a −/− (CLEC14A-KO) mice and wild-type mice. Middle cerebral artery occlusion surgery and behavioral assessments were performed to evaluate the neurologic damage. The change of tight junctional proteins, adhesion molecules, pro-inflammatory cytokines, and microglial were confirmed by immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction of brain samples. Results: In endothelial cells, knockdown of CLEC14A increased FITC-dextran permeability and decreased transendothelial electrical resistance; the severity of this effect increased with VEGF treatment. Immunofluorescence staining revealed that tight junctional proteins were attenuated in the CLEC14A knockdown endothelial cells. Consistent with the in vitro results, CLEC14A-KO mice that were injected with Evans blue dye had cerebral vascular leakage at postnatal day 8; wild-type mice had no leakage. We used a middle cerebral artery occlusion model and found that CLEC14A-KO mice had severe infarcted brain and neurological deficits with upregulated VEGFR-2 expression. FITC-dextran leakage was present in CLEC14A-KO mice after ischemia-reperfusion, and the numbers of tight junctional molecules were significantly decreased. Loss of CLEC14A increased the pro-inflammatory response through adhesion molecule expression, and glial cells were activated. Conclusions: These results suggest that activation of VEGFR-2 in CLEC14A-KO mice aggravates ischemic stroke by exacerbating cerebral vascular leakage and increasing neuronal inflammation after ischemia-reperfusion injury.

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Section: Introductionmentioning

confidence: 99%

CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation

Kim

Lee

Zhang

et al. 2020

J Neuroinflammation

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“…In this study, to further dissect out the specific contribution of HIF1α in neuronal cell death/survival, we used pharmacological strategies with a known HIF1α inhibitor 2-methoxyestradiol (2ME2), or a PHD inhibitor dimethyloxalylglycine (DMOG) that stabilizes HIF1α, to manipulate HIF1α levels in immature primary cortical neurons. We investigated whether acute manipulation of HIF1α expression has any impact on neuronal viability, as well as its effects on the HIF1α substrates, vascular endothelial growth factor (VEGF) and erythropoietin (Epo), both of which are proven to be beneficial in brain repair in rodent models of neonatal HI and neonatal stroke [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

HIF1α Signaling in the Endogenous Protective Responses after Neonatal Brain Hypoxia-Ischemia

Liang¹,

Liu²,

Lu³

et al. 2018

Dev Neurosci

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Hypoxia-inducible factor 1α (HIF1α) is a key regulator of oxygen homeostasis, and its target genes mediate adaptive, protective, and pathological processes. The role of HIF1α in neuronal survival is controversial and the brain maturation stage is important in determining its function in brain ischemia or hypoxia-ischemia (HI). In this study, we used neuronspecific HIF1α knockout mice at postnatal day 9 (P9), and immature cortical neurons (days 7-8 in vitro) treated with the HIF1α inhibitor 2-methoxyestradiol (2ME2) or stabilizer dimethyloxalylglycine (DMOG), to examine the function of neuronal HIF1α in neonatal HI in vivo (Vannucci model) and in vitro (oxygen glucose deprivation, OGD). Inhibition of HIF1α with 2ME2 in primary neurons or deletion of neuronal HIF1α in P9 mice increased both necrotic and apoptotic cell death following HI, as evaluated by the protein levels of 145/150-kDa and 120-kDa spectrin breakdown products 24 h after HI. DMOG attenuated neuronal death right after OGD. Acute pharmacological manipulation of HIF1α synchronous-ly regulated the expression of its targets, vascular endothelial growth factor (VEGF) and erythropoietin (Epo), in the same manner. The in vivo findings agree with our previous data using the same HIF1α-deficient mice at an earlier age. This study confirms the role of neuronal HIF1α signaling in the endogenous protective responses following HI in the developing brain.

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“…Acute stroke increases vascular permeability, and leaky blood vessels aggravate BBB disruption and edema (40). Thus, we used the I/R model to identify SALM4 functions in a pathologic condition (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Salm4 2/2 mice show ameliorated brain damage after I/R As mentioned above, SALM4-depleted ECs showed attenuated permeability through VEGFR2 phosphorylation at the Y1175-PI3K-AKT-eNOS signaling axis, which plays a role in acute brain stroke (39). Acute stroke increases vascular permeability, and leaky blood vessels aggravate BBB disruption and edema (40). Thus, we used the I/R model to identify SALM4 functions in a pathologic condition ( Supplemental Fig.…”

Section: Angiogenesis-related Gene Transcription Is Inhibited In Salmmentioning

confidence: 95%

SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175

et al. 2019

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Angiogenesis depends on VEGF-mediated signaling. However, the regulatory mechanisms and functions of individual VEGF receptor 2 (VEGFR2) phosphorylation sites remain unclear. Here, we report that synaptic adhesion-like molecule 4 (SALM4) regulates a specific VEGFR2 phosphorylation site. SALM4 silencing in HUVECs and Salm4 knockout (KO) in lung endothelial cells (ECs) of Salm4 −/− mice suppressed phosphorylation of VEGFR2 tyrosine (Y) 1175 (Y1173 in mice) and downstream signaling upon VEGF-A stimulation. However, VEGFR2 phosphorylation at Y951 (Y949 in mice) and Y1214 (Y1212 in mice) remained unchanged. Knockdown and KO of SALM4 inhibited VEGF-A–induced angiogenic functions of ECs. SALM4 depletion reduced endothelial leakage, sprouting, and migratory activities. Furthermore, in an ischemia and reperfusion (I/R) model, brain injury was attenuated in Salm4 −/− mice compared with wild-type (WT) mice. In brain lysates after I/R, VEGFR2 phosphorylation at Y949, Y1173, and Y1212 were induced in WT brains, but only Y1173 phosphorylation of VEGFR2 was reduced in Salm4 −/− brains. Taken together, our results demonstrate that SALM4 specifically regulates VEGFR2 phosphorylation at Y1175 (Y1173 in mice), thereby fine-tuning VEGF signaling in ECs.—Kim, D. Y., Park, J. A., Kim, Y., Noh, M., Park, S., Lie, E., Kim, E., Kim, Y.-M., Kwon, Y.-G. SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175.

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The Janus Face of VEGF in Stroke

Cited by 140 publications

References 182 publications

CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation

CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation

HIF1α Signaling in the Endogenous Protective Responses after Neonatal Brain Hypoxia-Ischemia

SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175

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