Sensory neurons from dorsal root ganglia regulate endothelial cell function in extracellular matrix remodelling
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(2020) 18:162
RESEARCH
Open Access
Sensory neurons from dorsal root ganglia regulate endothelial cell function in extracellular matrix remodelling Alice Leroux1* , Bruno Paiva dos Santos1, Jacques Leng2, Hugo Oliveira1 and Joëlle Amédée1
Abstract Background: Recent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown. Our previous work demonstrated that sensory neurons (SNs) induce the osteoblastic differentiation of mesenchymal stem cells, but the influence of SNs on endothelial cells (ECs) was not studied. Methods: Here, in order to study in vitro the interplay between SNs and ECs, we used microfluidic devices as an indirect co-culture model. Gene expression analysis of angiogenic markers, as well as measurements of metalloproteinases protein levels and enzymatic activity, were performed. Results: We were able to demonstrate that two sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were involved in the transcriptional upregulation of angiogenic markers (vascular endothelial growth factor, angiopoietin 1, type 4 collagen, matrix metalloproteinase 2) in ECs. Co-cultures of ECs with SNs also increased the protein level and enzymatic activity of matrix metalloproteinases 2 and 9 (MMP2/MMP9) in ECs. Conclusions: Our results suggest a role of sensory neurons, and more specifically of CGRP and SP, in the remodelling of endothelial cells extracellular matrix, thus supporting and enhancing the angiogenesis process. Keywords: Angiogenesis, Cellular communication, Innervation, Matrix Metalloproteinases, Extracellular matrix Remodelling, Neurovascular interplay
Background Bone is a dynamic tissue which is both vascularized [1– 3] and innervated [4–6]. Numerous evidence from animal studies that began in the 1980’s, suggest a relationship between sensory nerve damage and joint diseases [7–9]. The focus on skeletal neurobiology emerged with a series of sensory denervation experimental models performed mainly in rats [10, 11] and confirmed the role of peripheral innervation in the regulation of bone tissue development and regeneration. Nerve fibres exist * Correspondence: [email protected] 1 Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France Full list of author information is available at the end of the article
throughout bone but are more abundant in the periosteum, as well as in the mineralized and vascularized parts of bone tissue, and are predominantly located at metabolically active regions of bone [12–18]. More interestingly, nerves are closely associated with arteries and capillaries. Nerve fibres penetrate through the porous structures of the cancellous bone along with blood vessels, suggesting that they are closely linked to each other molecularly, functionally and anatomically [19, 20]. Important studies brought the attention to the effect of sensory innervation on osteogenesis and angiogenesis. A work published by Fukuda and co
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