Neurovascular Interaction Promotes the Morphological and Functional Maturation of Cortical Neurons

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2017 Oct 3

PMID 28966577

Citations 20

Authors

Kun-Wei Wu

Jia-Lin Mo

Zeng-Wei Kou

Qi Liu

Ling-Ling Lv

Yu Lei

Feng-Yan Sun

Affiliations

Soon will be listed here.

Abstract

Brain microvascular endothelial cells (BMEC) have been found to guide the migration, promote the survival and regulate the differentiation of neural cells. However, whether BMEC promote development and maturation of immature neurons is still unknown. Therefore, in this study, we used a direct endothelium-neuron co-culture system combined with patch clamp recordings and confocal imaging analysis, to investigate the effects of endothelial cells on neuronal morphology and function during development. We found that endothelial cells co-culture or BMEC-conditioned medium (B-CM) promoted neurite outgrowth and spine formation, accelerated electrophysiological development and enhanced synapse function. Moreover, B-CM treatment induced vascular endothelial growth factor (VEGF) expression and p38 phosphorylation in the cortical neurons. Through pharmacological analysis, we found that incubation with SU1498, an inhibitor of VEGF receptor, abolished B-CM-induced -p38 upregulation and suppressed the enhancement of synapse formation and transmission. SB203580, an inhibitor of p38 MAPK also blocked B-CM-mediated synaptic regulation. Together these results clearly reveal that the endothelium-neuron interactions promote morphological and functional maturation of neurons. In addition, neurovascular interaction-mediated promotion of neural network maturation relies on activation of VEGF/Flk-1/p38 MAPK signaling. This study provides novel aspects of endothelium-neuron interactions and novel mechanism of neurovascular crosstalk.

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References

Bolton M, Pittman A, Lo D . Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci. 2000; 20(9):3221-32. PMC: 6773110. View

Shen S, Duan C, Chen X, Wang Y, Sun X, Zhang Q . Neurogenic effect of VEGF is related to increase of astrocytes transdifferentiation into new mature neurons in rat brains after stroke. Neuropharmacology. 2015; 108:451-61. DOI: 10.1016/j.neuropharm.2015.11.012. View

Kim H, Li Q, Hempstead B, Madri J . Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells. J Biol Chem. 2004; 279(32):33538-46. DOI: 10.1074/jbc.M404115200. View

Origlia N, Righi M, Capsoni S, Cattaneo A, Fang F, Stern D . Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J Neurosci. 2008; 28(13):3521-30. PMC: 6670592. DOI: 10.1523/JNEUROSCI.0204-08.2008. View

Wu K, Kou Z, Mo J, Deng X, Sun F . Neurovascular coupling protects neurons against hypoxic injury via inhibition of potassium currents by generation of nitric oxide in direct neuron and endothelium cocultures. Neuroscience. 2016; 334:275-282. DOI: 10.1016/j.neuroscience.2016.08.012. View

Iadecola C . Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. 2004; 5(5):347-60. DOI: 10.1038/nrn1387. View

Huang Y, Yang C, Huang C, Tai M, Hsu K . Pharmacological and genetic accumulation of hypoxia-inducible factor-1alpha enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor. J Neurosci. 2010; 30(17):6080-93. PMC: 6632593. DOI: 10.1523/JNEUROSCI.5493-09.2010. View

Gama Sosa M, De Gasperi R, Rocher A, Perez G, Simons K, Cruz D . Interactions of primary neuroepithelial progenitor and brain endothelial cells: distinct effect on neural progenitor maintenance and differentiation by soluble factors and direct contact. Cell Res. 2007; 17(7):619-26. DOI: 10.1038/cr.2007.53. View

Ruiz de Almodovar C, Lambrechts D, Mazzone M, Carmeliet P . Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009; 89(2):607-48. DOI: 10.1152/physrev.00031.2008. View

10.

Makita T, Sucov H, Gariepy C, Yanagisawa M, Ginty D . Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons. Nature. 2008; 452(7188):759-63. PMC: 2713667. DOI: 10.1038/nature06859. View

11.

He Q, Li Q, Jin H, Zhi F, Suraj B, Zhu Y . MiR-150 Regulates Poststroke Cerebral Angiogenesis via Vascular Endothelial Growth Factor in Rats. CNS Neurosci Ther. 2016; 22(6):507-17. PMC: 6492828. DOI: 10.1111/cns.12525. View

12.

Lo E, Dalkara T, Moskowitz M . Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003; 4(5):399-415. DOI: 10.1038/nrn1106. View

13.

Whiteus C, Freitas C, Grutzendler J . Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period. Nature. 2013; 505(7483):407-11. PMC: 3947100. DOI: 10.1038/nature12821. View

14.

Kim B, Choi M, Kim Y, Park H, Lee H, Yun C . Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin. Cell Signal. 2008; 20(4):714-25. DOI: 10.1016/j.cellsig.2007.12.009. View

15.

Ullian E, Sapperstein S, Christopherson K, Barres B . Control of synapse number by glia. Science. 2001; 291(5504):657-61. DOI: 10.1126/science.291.5504.657. View

16.

Ruiz de Almodovar C, Coulon C, Salin P, Knevels E, Chounlamountri N, Poesen K . Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1. J Neurosci. 2010; 30(45):15052-66. PMC: 6633861. DOI: 10.1523/JNEUROSCI.0477-10.2010. View

17.

Shen Q, Goderie S, Jin L, Karanth N, Sun Y, Abramova N . Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004; 304(5675):1338-40. DOI: 10.1126/science.1095505. View

18.

Honma Y, Araki T, Gianino S, Bruce A, Heuckeroth R, Johnson E . Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron. 2002; 35(2):267-82. DOI: 10.1016/s0896-6273(02)00774-2. View

19.

Guo S, Kim W, Lok J, Lee S, Besancon E, Luo B . Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc Natl Acad Sci U S A. 2008; 105(21):7582-7. PMC: 2396701. DOI: 10.1073/pnas.0801105105. View

20.

Tam S, Watts R . Connecting vascular and nervous system development: angiogenesis and the blood-brain barrier. Annu Rev Neurosci. 2010; 33:379-408. DOI: 10.1146/annurev-neuro-060909-152829. View