VEGF/VEGFR2 signaling regulates hippocampal axon branching during development

Luck, Robert; Urban, Severino; Karakatsani, Andromachi; Harde, Eva; Sambandan, Sivakumar; Nicholson, LaShae; Haverkamp, Silke; Mann, Rebecca; Martín-Villalba, Ana; Schuman, Erin M.; Acker‐Palmer, Amparo; Almodóvar, Carmen Ruiz de

doi:10.7554/elife.49818

Cited by 24 publications

(19 citation statements)

References 44 publications

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“…VEGFR-2 mediates the main physiological functions of VEGF. VEGF, the vascular permeability factor (VPF), is an essential and crucial growth factor for vascular endothelial cells, and plays various roles in cardiovascular system ( Wang et al, 2019 ), central nervous system ( Bellon et al, 2010 ; Luck et al, 2019 ), hematopoiesis ( Hooper et al, 2009 ), development ( Karaman et al, 2018 ), and tumorigenesis ( Volz et al, 2020 ; Zhong et al, 2020 ). Despite having so many physiological functions, the main physiological functions of VEGF on endothelial cells are almost all achieved by activating VEGFR-2, including stimulating endothelial cell proliferation, increasing vascular permeability, and chemotaxis to endothelial cells, etc.…”

Section: Vegfr-2 Physiological Functions and Pathological Rolesmentioning

confidence: 99%

“…During embryonic development, the VEGFR-2 signaling pathway is involved in the proliferation, growth, and migration of hematopoietic and early endothelial cells (angioblasts) ( Dias et al, 2000 ; LeCouter et al, 2004 ). Several studies showed that the VEGF/VEGFR-2 signaling directly regulates the development and function of neurons, e.g., increased axon branching ( Luck et al, 2019 ).…”

Section: Vegfr-2 Physiological Functions and Pathological Rolesmentioning

confidence: 99%

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Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

Wang

Bove²,

Simone³

et al. 2020

Front. Cell Dev. Biol.

179

141

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The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) play crucial roles in vasculogenesis and angiogenesis. Angiogenesis is an important mechanism in many physiological and pathological processes, and is involved in endothelial cell proliferation, migration, and survival, then leads to further tubulogenesis, and finally promotes formation of vessels. This series of signaling cascade pathways are precisely mediated by VEGF/VEGFR-2 system. The VEGF binding to the IgD2 and IgD3 of VEGFR-2 induces the dimerization of the receptor, subsequently the activation and trans-autophosphorylation of the tyrosine kinase, and then the initiation of the intracellular signaling cascades. Finally the VEGF-activated VEGFR-2 stimulates and mediates variety of signaling transduction, biological responses, and pathological processes in angiogenesis. Several crucial phosphorylated sites Tyr801, Try951, Try1175, and Try1214 in the VEGFR-2 intracellular domains mediate several key signaling processes including PLCγ-PKC, TSAd-Src-PI3K-Akt, SHB-FAK-paxillin, SHB-PI3K-Akt, and NCK-p38-MAPKAPK2/3 pathways. Based on the molecular structure and signaling pathways of VEGFR-2, the strategy of the VEGFR-2-targeted therapy should be considered to employ in the treatment of the VEGF/VEGFR-2-associated diseases by blocking the VEGF/VEGFR-2 signaling pathway, inhibiting VEGF and VEGFR-2 gene expression, blocking the binding of VEGF and VEGFR-2, and preventing the proliferation, migration, and survival of vascular endothelial cells expressing VEGFR-2.

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Section: Vegfr-2 Physiological Functions and Pathological Rolesmentioning

confidence: 99%

Section: Vegfr-2 Physiological Functions and Pathological Rolesmentioning

confidence: 99%

Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

Wang

Bove²,

Simone³

et al. 2020

Front. Cell Dev. Biol.

179

141

View full text Add to dashboard Cite

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“…In addition, external cues that induce collaterals from sensory stem axons in the spinal cord have not yet been characterized. However, a recent study characterized VEGF and its receptor VEGFR2 in the hippocampus as an axon branching system (Luck and others 2019). Based on the expression of the VEGF in the spinal cord and its receptor VEGFR2 in DRG neurons at early stages of development, it would be of interest to investigate collateral branching from sensory stem axons in the spinal cord (Himmels and others 2017).…”

Section: Npr2-mediated Cgmp Signaling Does Not Regulate Collateral (Imentioning

confidence: 99%

Sensory Neurons: The Formation of T-Shaped Branches Is Dependent on a cGMP-Dependent Signaling Cascade

2020

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Axon bifurcation – a specific form of branching of somatosensory axons characterized by the splitting of the growth cone – is mediated by a cGMP-dependent signaling cascade composed of the extracellular ligand CNP (C-type natriuretic peptide), the transmembrane receptor guanylyl cyclase Npr2 (natriuretic peptide receptor 2), and the kinase cGKI (cGMP-dependent protein kinase I). In the absence of any one of these components, the formation of T-shaped axonal branches is impaired in neurons from DRGs (dorsal root ganglia), CSGs (cranial sensory ganglia) and MTNs (mesencephalic trigeminal neurons) in the murine spinal cord or hindbrain. Instead, axons from DRGs or from CSGs extend only either in an ascending or descending direction, while axons from MTNs either elongate within the hindbrain or extend via the trigeminal ganglion to the masseter muscles. Collateral formation from non-bifurcating stem axons is not affected by impaired cGMP signaling. Activation of Npr2 requires both binding of the ligand CNP as well as phosphorylation of serine and threonine residues at the juxtamembrane regions of the receptor. The absence of bifurcation results in an altered shape of termination fields of sensory afferents in the spinal cord and resulted in impaired noxious heat sensation and nociception whereas motor coordination appeared normal.

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“…This study was novel in investigating the correlation between CBF based on 3D-ASL, VEGF expression, and cognition in a T2DM rat model. However, it had certain limitations: (1) Previous studies revealed that the effect of VEGF expression on memory was primarily a result of axonal loss, demyelination, or changing plasticity of mature neurons[ 12 , 39 , 47 ]. The possibility that the decreased VEGF level might cause DACD via hippocampal neural injury was not examined in the present study; and (2) Previous findings indicated that each division of the hippocampus had different functions[ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Vascular endothelial growth factor (VEGF; also known as VEGF-A) is involved in microvascular structure and function and the development of axon branching[ 11 , 12 ]. Many studies have shown that enhancing VEGF signaling or VEGF restoration can ameliorate cognitive function[ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

Shao

Wang

Yang

et al. 2021

WJD

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BACKGROUND Type 2 diabetes mellitus (T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia. The mechanisms of diabetes-associated cognitive dysfunction (DACD) have not been fully elucidated to date. Some studies proved lower cerebral blood flow (CBF) in the hippocampus was associated with poor executive function and memory in T2DM. Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor (VEGF) expression and CBF changes in humans and animal models. In this study, we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional (3D) arterial spin labeling (3D-ASL) and VEGF expression in the hippocampus. AIM To assess the correlation between CBF (measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM. METHODS Forty Sprague-Dawley male rats were divided into control and T2DM groups. The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM. Cognitive function was assessed using the Morris water maze experiment. The CBF changes were measured by 3D-ASL magnetic resonance imaging. VEGF expression was determined using immunofluorescence. RESULTS The escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group. The total distance traveled was longer in the T2DM group; also, the platform was crossed fewer times. The percentage of distance in the target zone significantly decreased. CBF decreased in the bilateral hippocampus in the T2DM group. No difference was found between the right CBF value and the left CBF value in the T2DM group. The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value. The escape latency negatively correlated with the CBF value. The number of rats crossing the platform positively correlated with the CBF value. CONCLUSION Low CBF in the hippocampus and decreased VEGF expression might be crucial in DACD. CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.

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VEGF/VEGFR2 signaling regulates hippocampal axon branching during development

Cited by 24 publications

References 44 publications

Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

Sensory Neurons: The Formation of T-Shaped Branches Is Dependent on a cGMP-Dependent Signaling Cascade

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

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