Paradoxical effects of VEGF on synaptic activity partially involved in notch1 signaling in the mouse hippocampus.
It is well known that the neuronal effects of vascular endothelial growth factor (VEGF) include modulating learning and memory, plasticity of mature neurons, and synaptic transmission in addition to neurogenesis. However, there is conflicting evidence particularly of its role in the regulation of excitatory synaptic activity. In this study, application of the patch-clamp technique revealed that lower doses (10 and 50 ng/mL) of VEGF enhanced excitatory neurotransmission in hippocampal slices of mice through both presynaptic and postsynaptic mechanisms. However, the effects were reversed by higher doses of VEGF (>100 ng/mL), which inhibited excitatory neurotransmission via a presynaptic mechanism. These competing, concentration-dependent effects of VEGF suggested that different pathways were involved. The involvement of the Notch1 receptor was tested in the modulation of VEGF on synaptic activity by using heterozygous Notch1(+/-) mice. Notch1 knockdown did not influence the inhibitory effect of high VEGF doses (200 ng/mL) but reduced the enhancement effects of low concentration of VEGF (50 ng/mL) at the postsynaptic level, which might be due to the decreased level of VEGF receptor. The results indicate that the Notch1 receptor plays a role in VEGF-induced modulation of synaptic activity, which provides new insights into a complex VEGF/Notch signaling cross-talk. These findings set the groundwork for understanding new mechanisms of Notch signaling and the neurotrophic effects of VEGF, which is beneficial to develop new therapeutic targets to the VEGF/Notch axis and improve current treatments for neural diseases.
School of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, Tianjin, 300071, China.|Tianjin University, Tianjin, 300072, China.
Jiajia
J
Yang
School of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, Tianjin, 300071, China.
Chunxiao
C
Yang
School of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, Tianjin, 300071, China.
Chunhua
C
Liu
College of Life Science, Nankai University, Tianjin, 300071, China.
Tao
T
Zhang
School of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, Tianjin, 300071, China.
Zhuo
Z
Yang
D000818:Animals; D000831:Animals, Newborn; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051881:Receptor, Notch1 / Q000172:deficiency* / Q000235:genetics; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
EPSCs; Notch1 receptor; VEGF; cross-talk; synaptic transmission; whole-cell patch-clamp