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 p-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.
Highlights
It has been well known that neurovascular interaction plays important roles in the development of brain architecture and its function in the mammalian (Iadecola, 2004; Stubbs et al, 2009; Eichmann and Thomas, 2013; Andreone et al, 2015)
With a direct co-culture model combined with electrophysiological recordings and confocal imaging analysis, we discovered that brain endothelial cells directly promoted neurite outgrowth of cortical neurons in the early stage of in vitro development and enhanced synapse formation and transmission via vascular endothelial growth factor (VEGF)/Flk-1/p38 MAPK signaling in the later stage of in vitro development
We found that Brain microvascular endothelial cells (BMEC) co-culture or BMEC-conditioned medium (B-CM) treatment increased neurite length and complexity, compared with neurons cultured alone in the early stage (1–3 days in vitro (DIV)) of in vitro development (Figure 1)
Summary
It has been well known that neurovascular interaction plays important roles in the development of brain architecture and its function in the mammalian (Iadecola, 2004; Stubbs et al, 2009; Eichmann and Thomas, 2013; Andreone et al, 2015). Neurovascular Interaction Promotes Neuron Maturation vessel outgrowth (Autiero et al, 2005; Tam and Watts, 2010) and vascular-derived signals, such as artemin and endothelin, involve in axonal guidance (Honma et al, 2002; Makita et al, 2008). It has been reported that endothelial cells enhance neurogenesis and migration of neurons in co-cultured subependymal zone explants (Leventhal et al, 1999) and accelerate neurite outgrowth of newborn neurons in co-cultured spinal motor neurons (Dugas et al, 2008). These observations suggest that neural and vascular cells form a functionally integrated network in the developing CNS. Whether brain endothelial cells promote maturation of neurons and regulate function of brain neural network during postnatal development under physiological conditions
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