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 (Biol Open 2015). 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 a central role in cytoskeletal changes, is required for endothelial sprouting (Dev Biol. 2016). 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) The neuro-vascular network influences organ physiology, regeneration, and diseases. 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 ear skin regeneration/wound healing. 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 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 (Manuscript in Revision). This discovery has profound implications for the study of neo-vascularization in pathological conditions including wound healing and cancer.
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