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Hiroyasu Kidoya
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Takara, K.;  Hayashi-Okada, Y.;  Kidoya, H. Formation of Arteries and Veins by Nerve–Vessel Interaction. Encyclopedia. Available online: https://encyclopedia.pub/entry/40655 (accessed on 15 July 2025).
Takara K,  Hayashi-Okada Y,  Kidoya H. Formation of Arteries and Veins by Nerve–Vessel Interaction. Encyclopedia. Available at: https://encyclopedia.pub/entry/40655. Accessed July 15, 2025.
Takara, Kazuhiro, Yumiko Hayashi-Okada, Hiroyasu Kidoya. "Formation of Arteries and Veins by Nerve–Vessel Interaction" Encyclopedia, https://encyclopedia.pub/entry/40655 (accessed July 15, 2025).
Takara, K.,  Hayashi-Okada, Y., & Kidoya, H. (2023, January 31). Formation of Arteries and Veins by Nerve–Vessel Interaction. In Encyclopedia. https://encyclopedia.pub/entry/40655
Takara, Kazuhiro, et al. "Formation of Arteries and Veins by Nerve–Vessel Interaction." Encyclopedia. Web. 31 January, 2023.
Formation of Arteries and Veins by Nerve–Vessel Interaction
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This entry is adapted from the peer-reviewed paper 10.3390/life13010042

Vertebrates use a network of blood vessels and nerves to perform complex higher-order functions and maintain homeostasis. The 16th-century anatomical text "De humani corporis fabrica" describes blood vessel and nerve networks with a branching pattern that is closely aligned and parallel. This close interaction between adjacent blood vessels and nerves is necessary for organogenesis, tissue repair, homeostasis, and functional expression. Neurovascular disruptions also promote disease progression, including cancer. Thus, researchers highlight the advances in vascular biology research, particularly neurovascular interactions. 

blood vessels vascular patterning angiogenesis

1. Regulation of Arterial Patterning

The immature vascular plexus formed by angiogenesis and vasculogenesis matures into a hierarchical vascular structure composed of arteries, veins, and capillaries through vascular remodelling. Sensory nerve fibres have been shown to regulate the formation of blood vessels and branching patterns in foetal mouse skin vascular remodelling. In the process of skin vascular and neural network formation in foetal mice, an immature vascular plexus is initially formed around embryonic day 11 via angiogenesis and vasculogenesis. On embryonic day 13, the peripheral nervous system sensory nerve fascicles extend their axons and form a neural network within the vascular plexus. Subsequently, arteriolar vessels develop in parallel with the branching pattern of sensory nerve fascicles [1]. In this instance, peripheral nerve fascicles and arterial blood vessels do not adhere to one another but rather form structures that run together at regular intervals. Neurogenin1/Neurogenin2 double-knockout animals, in which sensory nerve fibres and non-myelin Schwann cells are lacking, exhibit a disorganised vascular branching pattern with reduced maturation of the cutaneous vascular network [2]. In addition, the importance of non-myelin Schwann-cell-derived signals in the formation of vascular branching patterns has been demonstrated by its absence and the lack of concomitant peripheral nerve fascicles and blood vessels in the foetal skin of ErbB3 knockout mice. In contrast, it has been reported that in the foetal skin of Sema3A-deficient mice, where the cutaneous sensory nerve network is constructed in a disorganised manner, arterial vessels run parallel to the disorganised branching pattern of sensory nerve fibres [3]. In other words, the branching pattern of sensory nerve fascicles serves as a template for the branching pattern of blood vessels (Figure 1). The expression of chemokine CXCL12 from sensory nerve fascicles regulates arterial branching patterns in sensory nerve fibres. The action of secreted CXCL12 on CXCR4 receptors specifically expressed on vascular endothelial cells induces the migration of vascular endothelial cells of the adjacent atrial vascular plexus towards the sensory nerve fascicle. As indicated by the disruption of the parallel structure of peripheral nerve fascicles and blood vessels in the foetal skin of Cxcl12 and Cxcr4 knockout mice, CXCL12–CXCR4 signalling is involved in the regulation of vascular branching patterns by sensory nerve fascicles [4].
Figure 1. Neurovascular interactions induce the formation of arteries and veins. (a) Peripheral sensory nerve fascicles invading the primary vascular plexus produce VEGFA, which stimulates the arterialisation of nearby capillary. Parallel arterial–vein branching patterns are completed when Cxcl12 wires differentiated arteries into the vicinity of sensory nerve fascicles. (b) A part of the primitive vascular plexus then develops venous differentiation, and veins migrate towards the arteries by the effect of apelin produced by the arteries on APJ expressed in the veins. The veins mature as they migrate, and eventually, a parallel structure of nerves, arteries, and veins is established.

2. Regulation of Arterial Differentiation

It is believed that arteries and veins differentiate in response to physical stimuli produced by heartbeat and blood flow. However, the membrane-bound ligand ephrin B2 and its tyrosine kinase-type receptor EphB4, which are molecular markers in arteries and veins, are specifically expressed during the formation of the primary vascular plexus. Hence, it is possible that the fate of arteriovenous vessels is decided earlier than blood flow, although it has been demonstrated that the various signals received later are just as vital.
Activation of notch signalling by VEGFA is essential for arterial vascular endothelial cell differentiation [5]. The phospholipase C-γ (PLC-γ)-mitogen-activated protein kinase (MAPK) pathway, which is activated downstream of VEGFR2, is responsible for arterial differentiation [6]. VEGFA signalling affects arterial development by upregulating notch ligand Dll4 expression [7][8]. Upregulation of the Fox family transcription factors Foxc1 and Foxc2 is involved in artery formation by enhancing the expression of Dll4, Notch1, Notch4, and ephrin B2 [9]. Studies with knockout mice have demonstrated that Dll4-Notch1/4 signalling regulates Hey1/2 expression via RBP-J to influence arterial differentiation [10]. Furthermore, notch signalling has been shown to affect arteriogenesis by regulating CD36 expression [11].
During the development of arterioles in the skin, sensory-nerve-fascicle-derived “VEGF-A” promotes arterialisation of capillary endothelial cells by activating VEGFR2–neuregulin 1 receptor signalling (Figure 1). In sensory-nerve-fascicle-specific Vegfa knockout mice and vascular endothelium-specific neuropilin 1 knockout mice, arterial differentiation in the proximity of nerve fascicles is inhibited. It has been hypothesised that peripheral-nerve-derived VEGFA promotes arterial formation by increasing the sensitivity of vascular endothelial cells expressing VEGFR2 and NRP1 [4]. During the development of foetal mouse arteries, Cxcr4-expressing vascular endothelial cells are initially attracted by Cxcl12 produced by non-myelin Schwann cells in the sensory nerve fascicles. Subsequently, Vegfa surrounding the nerve fascicle induces arterialisation of attracted vascular endothelial cells. Thus, the coordinated action of Vegfa and Cxcl12 generates a branching pattern of arterial vessels that parallels peripheral sensory nerve fascicles.

3. Regulation of Venous Differentiation and Patterning

Although the mechanism of arterial endothelial cell differentiation has been elucidated, the specifics of venous endothelial cell differentiation remain unclear. The nuclear receptor COUPTF2 regulates venous endothelial cell differentiation by suppressing Notch signalling through NRP1 repression [12][13]. Consequently, venous determinants may acquire venous specificity by inhibiting arterial determinants. Furthermore, bone morphogenetic protein (BMP) signalling acts on venous differentiation by inducing EPHB4 expression through ALK3/BMPR1A receptors and SMAD1/SMAD5 signalling [14]. Arteriovenous differentiation is predicted to be regulated by specific factors and their identification is anticipated.
The branching pattern of veins that runs parallel to the arterial pattern develops after sensory nerve fascicles and arteries are formed. The arteriole–vein juxtaposition structure is formed by the production of the bioactive peptide apelin from the artery and its action on the apelin receptor (APJ) expressed in the vein (Figure 1). Activation of APJ increases the motility of vascular endothelial cells and promotes the secretion of Wnt-related protein SFRP1. This causes myeloid cells to produce matrix metalloproteinases, hence, degradation of collagen that anchors the veins causing it to migrate towards the arterial side [15]. Furthermore, DROSHA, a microRNA biosynthetic enzyme that regulates the TGF-β and BMP pathways via miRNAs, has been shown to be involved in the formation of venous branching patterns as its knockout mice demonstrate disrupted arterial and venous juxtaposition structures [16]. The counter-current heat exchange between adjacent arteries and veins enables thermostatic animals to adapt to environmental temperatures [17]. Owing to the interdependence of nerves and blood vessels, nerves define the vascular network, whereas blood vessels define the neural network. In either case, the wiring between the nerves and blood vessels is a result of their close relationship. Analysis of single-cell RNA sequencing data has recently offered molecular insights into arterial, capillary, and venous differentiation, and it is anticipated that this information can be used to advance the understanding of the relationship between nerves and arteriovenous development [18].

References

  1. James, J.M.; Mukouyama, Y.S. Neuronal action on the developing blood vessel pattern. Semin. Cell Dev. Biol. 2011, 22, 1019–1027.
  2. Mukouyama, Y.S.; Shin, D.; Britsch, S.; Taniguchi, M.; Anderson, D.J. Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 2002, 109, 693–705.
  3. Li, W.; Kohara, H.; Uchida, Y.; James, J.M.; Soneji, K.; Cronshaw, D.G.; Zou, Y.R.; Nagasawa, T.; Mukouyama, Y.S. Peripheral nerve-derived CXCL12 and VEGF-A regulate the patterning of arterial vessel branching in developing limb skin. Dev. Cell 2013, 24, 359–371.
  4. Mukouyama, Y.S.; Gerber, H.P.; Ferrara, N.; Gu, C.; Anderson, D.J. Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin 1-mediated positive feedback. Development 2005, 132, 941–952.
  5. Lawson, N.D.; Vogel, A.M.; Weinstein, B.M. sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev. Cell 2002, 3, 127–136.
  6. Lawson, N.D.; Mugford, J.W.; Diamond, B.A.; Weinstein, B.M. Phospholipase C gamma-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 2003, 17, 1346–1351.
  7. Liu, Z.J.; Shirakawa, T.; Li, Y.; Soma, A.; Oka, M.; Dotto, G.P.; Fairman, R.M.; Velazquez, O.C.; Herlyn, M. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: Implications for modulating arteriogenesis and angiogenesis. Mol. Cell. Biol. 2003, 23, 14–25.
  8. Noguera-Troise, I.; Daly, C.; Papadopoulos, N.J.; Coetzee, S.; Boland, P.; Gale, N.W.; Lin, H.C.; Yancopoulos, G.D.; Thurston, G. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 2006, 444, 1032–1037.
  9. Seo, S.; Fujita, H.; Nakano, A.; Kang, M.; Duarte, A.; Kume, T. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev. Biol. 2006, 294, 458–470.
  10. Fischer, A.; Schumacher, N.; Maier, M.; Sendtner, M.; Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 2004, 18, 901–911.
  11. Jabs, M.; Rose, A.J.; Lehmann, L.H.; Taylor, J.; Moll, I.; Sijmonsma, T.P.; Herberich, S.E.; Sauer, S.W.; Poschet, G.; Federico, G.; et al. Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart. Circulation 2018, 137, 2592–2608.
  12. Tang, K.; Rubenstein, J.L.; Tsai, S.Y.; Tsai, M.J. COUP-TFII controls amygdala patterning by regulating neuropilin expression. Development 2012, 139, 1630–1639.
  13. You, L.R.; Lin, F.J.; Lee, C.T.; DeMayo, F.J.; Tsai, M.J.; Tsai, S.Y. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 2005, 435, 98–104.
  14. Neal, A.; Nornes, S.; Payne, S.; Wallace, M.D.; Fritzsche, M.; Louphrasitthiphol, P.; Wilkinson, R.N.; Chouliaras, K.M.; Liu, K.; Plant, K.; et al. Venous identity requires BMP signalling through ALK3. Nat. Commun. 2019, 10, 453.
  15. Kidoya, H.; Naito, H.; Muramatsu, F.; Yamakawa, D.; Jia, W.; Ikawa, M.; Sonobe, T.; Tsuchimochi, H.; Shirai, M.; Adams, R.H.; et al. APJ Regulates Parallel Alignment of Arteries and Veins in the Skin. Dev. Cell 2015, 33, 247–259.
  16. Jiang, X.; Wooderchak-Donahue, W.L.; McDonald, J.; Ghatpande, P.; Baalbaki, M.; Sandoval, M.; Hart, D.; Clay, H.; Coughlin, S.; Lagna, G.; et al. Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia. Sci. Signal. 2018, 11, eaan6831.
  17. Kahn, M.L. Vascular development for climate control. Dev. Cell 2015, 33, 241–242.
  18. Kalucka, J.; de Rooij, L.P.M.H.; Goveia, J.; Rohlenova, K.; Dumas, S.J.; Meta, E.; Conchinha, N.V.; Taverna, F.; Teuwen, L.A.; Veys, K.; et al. Single-Cell Transcriptome Atlas of Murine Endothelial Cells. Cell 2020, 180, 764–779.
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Subjects: Developmental Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Kazuhiro Takara
,
Yumiko Hayashi-Okada
,
Hiroyasu Kidoya
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Revisions: 2 times (View History)
Update Date: 01 Feb 2023
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