We here use the skin vasculature model as a favorable model system to study mechanisms that coordinate arterial differentiation and patterning of vascular branching. We previously observed that arterial vessels and peripheral sensory nerves (PNs) develop alongside each other in the embryonic limb skin. This co-patterning is developed by PN-mediated signal(s) that instructively guide the arterial branching network (Mukouyama et al. 2002). Therefore, the limb skin vasculature affords an attractive system in which to study the nature of neuronal signals that control vascular network formation. Using the tissue-specific knockout technology, we have begun to dissect out the PN-derived signals that participate in integrating both branching networks. We showed that PN-derived vascular endothelial growth factor (VEGF)-A functions to control arteriogenesis-arterial differentiation and smooth muscle cell association (Mukouyama et al. 2005). We have recently discovered that PN-derived C-X-C motif chemokine ligand (CXCL) 12 controls the nerve-blood vessel alignment. Our data establish that two distinct mechanisms underlie the congruence of nerve and arterial vessel branching: VEGF-A controlling arterial differentiation, and Cxcl12 controlling vessel branching and alignment with nerves (Li et al. 2013). In a similar line of research, we discovered that glial integrins in nerves modulates TGF that, in turn, influences lymphatic vessel development in the skin. Further genetic studies demonstrated that TGF signaling controls sprouting lymphangiogenesis (James et al. 2013). These findings suggest a novel, unifying concept involved in both angiogenesis and lymphangiogenesis: a coordinated local action of patterning and differentiation mechanisms, mediated by tissue substructures, such as peripheral nerves, underlies organ-specific vascular patterns. We are engaged in a new project for studying the role of the neuro-vascular association during tissue repair or in disease conditions. Whole-mount immunofluorescence microscopy has revealed that adult ear skin maintains the neuro-vascular bundle, suggesting that the association reflects the mutual requirement of nerve and vessel in the function and maintenance of both networks. Using this adult ear skin vasculature model, we are currently studying peripheral nerve regeneration and re-vascularization in the ear skin regeneration/wound healing.

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National Heart, Lung, and Blood Institute
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Fatima, Anees; Wang, Ying; Uchida, Yutaka et al. (2016) Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation. J Clin Invest 126:2437-51
Nohata, Nijiro; Uchida, Yutaka; Stratman, Amber N et al. (2016) Temporal-specific roles of Rac1 during vascular development and retinal angiogenesis. Dev Biol 411:183-94
Hatch, John; Mukouyama, Yoh-Suke (2015) Spatiotemporal mapping of vascularization and innervation in the fetal murine intestine. Dev Dyn 244:56-68
Uchida, Yutaka; James, Jennifer M; Suto, Fumikazu et al. (2015) Class 3 semaphorins negatively regulate dermal lymphatic network formation. Biol Open 4:1194-205
Mukouyama, Yoh-suke (2014) Vessel-dependent recruitment of sympathetic axons: looking for innervation in all the right places. J Clin Invest 124:2855-7
Mikelis, Constantinos M; Palmby, Todd R; Simaan, May et al. (2013) PDZ-RhoGEF and LARG are essential for embryonic development and provide a link between thrombin and LPA receptors and Rho activation. J Biol Chem 288:12232-43
James, Jennifer M; Nalbandian, Ani; Mukouyama, Yoh-suke (2013) TGFβ signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin. Development 140:3903-14
Xiao, Ying; Woo, Wei-Meng; Nagao, Keisuke et al. (2013) Perivascular hair follicle stem cells associate with a venule annulus. J Invest Dermatol 133:2324-31
Li, Wenling; Kohara, Hiroshi; Uchida, Yutaka et al. (2013) Peripheral nerve-derived CXCL12 and VEGF-A regulate the patterning of arterial vessel branching in developing limb skin. Dev Cell 24:359-71
Morrisey, Edward E; Cardoso, Wellington V; Lane, Robert H et al. (2013) Molecular determinants of lung development. Ann Am Thorac Soc 10:S12-6

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