Our principal accomplishments and on-going projects during the last year have been: 1) Neuronal guidance signals influence sprouting angiogenesis and lymphangiogenesis. The goal of our first project is to understand the multiple guidance cues that precisely coordinate endothelial sprouting. Our studies with high-resolution whole-mount skin staining and 3D culture systems revealed that Semaphorin 3F/3G negatively regulates venous and lymphatic endothelial sprouting through its receptor complex Neuropilin2/PlexinAs (Uchida et al. 2015 Biol Open). These studies pose a fundamental question as to the identity of the intracellular signaling pathway that transduces these signals and orients endothelial cell movements during endothelial sprouting. In collaboration, we discovered that Rac1, a Rho GTPase family member that serves as a central role in cytoskeletal changes, is required for endothelial sprouting (Nohata et al. 2016 Dev Biol). This project establishes an important foundation for understanding how collective and coordinated endothelial cell movements lead to a primary capillary network formation in development and cancer. 2) Neuro-vascular networks in pathological situations including obesity-related nerve disorders. We are engaged in a new project for studying what happens to the neuro-vascular networks in hyperglycemic animal models such as diet-induced obesity (DIO) mice and leptin receptor-deficient db/db mice, a severe obese and type 2 diabetic mouse model. We have developed a high-resolution whole-mount imaging method to analyze neuro-vascular braching in the entire ear skin of adult mice. This method enabled us to visualize branching morphogenesis and patterning of peripheral nerves and blood vessels in the adult ear skin, with comprehensive quantification measurements (Yamazaki et al. Submitted). Our ongoing studies show that our whole-mount imaging method enables us to investigate the neuro-vascular and neuro-immune phenotypes in animal models of obesity and diabetes. 3) Contribution of non-vascular cells in organ-specific vascular development. How are the multiple vascular cell types (endothelial cells, pericytes, and VSMCs) assembled to form an organ-specific vascular network? Are non-vascular origins involved in the vascular development? Our studies demonstrated that there are tissue-localized myeloid progenitor-derived pericytes in the vasculature of the ectoderm-derived tissues such as skin and brain. Further genetic studies revealed that TGF- influences differentiation of myeloid progenitors into pericytes (Yamazaki et al. 2017 Cell Rep). This discovery has profound implications for the study of neo-vascularization in pathological conditions including wound healing and cancer.
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