Agnieszka Dejda1, Gaelle Mawambo2, Jean-Francois Daudelin3, Khalil Miloudi4, Naoufal Akla5, Chintan Patel5, Elisabeth M M A Andriessen5, Nathalie Labrecque3, Florian Sennlaub6, Przemyslaw Sapieha1. 1. Department of Biochemistry and Molecular Medicine, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada 2Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montrea. 2. Department of Biochemistry and Molecular Medicine, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada. 3. Department of Medicine Microbiology, Infectiology and Immunology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada. 4. Department of Neurology-Neurosurgery, McGill University, Montreal, Quebec, Canada. 5. Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada. 6. Institut National de la Santé et de la Recherche Médicale, Paris, France 6Institut de la Vision, Paris, France.
Abstract
PURPOSE: Neuropilin-1 (NRP-1) is a transmembrane receptor that is critical for vascular development within the central nervous system (CNS). It binds and influences signaling of several key angiogenic factors, such as VEGF-165, semaphorin 3A, platelet derived growth factor, and more. Neuropilin-1 is expressed by neurons and endothelial cells as well as a subpopulation of proangiogenic macrophages/microglia that are thought to interact with endothelial tip cells to promote vascular anastomosis during brain vascularization. We previously demonstrated a significant role for NRP-1 in macrophage chemotaxis and showed that NRP-1-expressing microglia are major contributors to pathologic retinal angiogenesis. Given this influence on CNS angiogenesis, we now investigated the involvement of microglia-resident NRP-1 in developmental retinal vascularization. METHODS: We followed NRP-1 expressing microglia during retinal development. We used LysM-cre myeloid lineage-driver cre mice to reduce expression of NRP-1 in retinal myeloid-derived cells and performed a comprehensive morphometric analysis of retinal vasculature during development. RESULTS: We provide evidence that NRP-1+ microglia are present throughout the retina during vascular development with a preference for the non-vascularized retina. Using LysM-Cre/Nrp1(fl/fl) mice, we reduced NRP-1 expression by ~65% in retinal microglia and demonstrate that deficiency in NRP-1 in these microglia does not impair retinal angiogenesis. CONCLUSIONS: Our data draw a dichotomous role for NRP-1 in cells of myeloid lineage where it is dispensable for adequate retinal developmental vascularization yet obligate for pathologic retinal angiogenesis.
PURPOSE:Neuropilin-1 (NRP-1) is a transmembrane receptor that is critical for vascular development within the central nervous system (CNS). It binds and influences signaling of several key angiogenic factors, such as VEGF-165, semaphorin 3A, platelet derived growth factor, and more. Neuropilin-1 is expressed by neurons and endothelial cells as well as a subpopulation of proangiogenic macrophages/microglia that are thought to interact with endothelial tip cells to promote vascular anastomosis during brain vascularization. We previously demonstrated a significant role for NRP-1 in macrophage chemotaxis and showed that NRP-1-expressing microglia are major contributors to pathologic retinal angiogenesis. Given this influence on CNS angiogenesis, we now investigated the involvement of microglia-resident NRP-1 in developmental retinal vascularization. METHODS: We followed NRP-1 expressing microglia during retinal development. We used LysM-cre myeloid lineage-driver cre mice to reduce expression of NRP-1 in retinal myeloid-derived cells and performed a comprehensive morphometric analysis of retinal vasculature during development. RESULTS: We provide evidence that NRP-1+ microglia are present throughout the retina during vascular development with a preference for the non-vascularized retina. Using LysM-Cre/Nrp1(fl/fl) mice, we reduced NRP-1 expression by ~65% in retinal microglia and demonstrate that deficiency in NRP-1 in these microglia does not impair retinal angiogenesis. CONCLUSIONS: Our data draw a dichotomous role for NRP-1 in cells of myeloid lineage where it is dispensable for adequate retinal developmental vascularization yet obligate for pathologic retinal angiogenesis.
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