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 (manuscript in submission). 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. This also suggests a new concept in angiogenesis: coordinated local action of patterning and differentiation mechanisms, mediated by tissue sub-structures, such as peripheral nerves, underlies organotypic patterns of vascularization. The skin vasculature model also allows us to study the contribution of tissue macrophages in vascular development. We are particularly interested in how tissues macrophages influence dynamics of pericyte recruitment and function in the developing skin vasculature. Our whole-mount imaging approach of the skin lymphatic vasculature reveals cellular dynamics of architectural lymphatic vessel patterning. We are currently examining intercellular signaling that governs lymphatic vessel development. 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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Yamazaki, Tomoko; Mukouyama, Yoh-Suke (2018) Tissue Specific Origin, Development, and Pathological Perspectives of Pericytes. Front Cardiovasc Med 5:78
Yamazaki, Tomoko; Li, Wenling; Mukouyama, Yoh-Suke (2018) Whole-mount Confocal Microscopy for Adult Ear Skin: A Model System to Study Neuro-vascular Branching Morphogenesis and Immune Cell Distribution. J Vis Exp :
Yamazaki, Tomoko; Li, Wenling; Yang, Ling et al. (2018) Whole-Mount Adult Ear Skin Imaging Reveals Defective Neuro-Vascular Branching Morphogenesis in Obese and Type 2 Diabetic Mouse Models. Sci Rep 8:430
Yamazaki, Tomoko; Nalbandian, Ani; Uchida, Yutaka et al. (2017) Tissue Myeloid Progenitors Differentiate into Pericytes through TGF-? Signaling in Developing Skin Vasculature. Cell Rep 18:2991-3004
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 411:183-194
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
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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