Laura Beth Payne1, Bhanu P Tewari2, Logan Dunkenberger1, Samantha Bond1, Alyssa Savelli3, Jordan Darden1,4, Huaning Zhao1,5, Caroline Willi1, Ronak Kanodia1, Rosalie Gude1, Michael D Powell6, Kenneth J Oestreich6, Harald Sontheimer2, Sophie Dal-Pra7,8, John C Chappell1,3,5. 1. Center for Vascular and Heart Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke (L.B.P., L.D., S.B., A.S., J.D., H.Z., C.W., R.K., R.G., J.C.C.). 2. Department of Neuroscience, University of Virginia, Charlottesville (B.P.T., H.S.). 3. Virginia Tech Carilion School of Medicine, Roanoke (A.S., J.C.C.). 4. Graduate Program in Translational Biology, Medicine and Health (J.D.), Virginia Tech, Blacksburg. 5. Department of Biomedical Engineering and Mechanics (H.Z., J.C.C.), Virginia Tech, Blacksburg. 6. Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus (M.D.P., K.J.O.). 7. Division of Cardiovascular Medicine and Mandel Center for Hypertension Research (S.D.-P.), Duke University Medical Center, Durham, NC. 8. Division of Cardiovascular Medicine, Department of Medicine (S.D.-P.), Duke University Medical Center, Durham, NC.
Abstract
BACKGROUND: Vascular pericytes stabilize blood vessels and contribute to their maturation, while playing other key roles in microvascular function. Nevertheless, relatively little is known about involvement of their precursors in the earliest stages of vascular development, specifically during vasculogenesis. METHODS: We combined high-power, time-lapse imaging with transcriptional profiling of emerging pericytes and endothelial cells in reporter mouse and cell lines. We also analyzed conditional transgenic animals deficient in Cx43/Gja1 (connexin 43/gap junction alpha-1) expression within Ng2+ cells. RESULTS: A subset of Ng2-DsRed+ cells, likely pericyte/mural cell precursors, arose alongside endothelial cell differentiation and organization and physically engaged vasculogenic endothelium in vivo and in vitro. We found no overlap between this population of differentiating pericyte/mural progenitors and other lineages including hemangiogenic and neuronal/glial cell types. We also observed cell-cell coupling and identified Cx43-based gap junctions contributing to pericyte-endothelial cell precursor communication during vascular assembly. Genetic loss of Cx43/Gja1 in Ng2+ pericyte progenitors compromised embryonic blood vessel formation in a subset of animals, while surviving mutants displayed little-to-no vessel abnormalities, suggesting a resilience to Cx43/Gja1 loss in Ng2+ cells or potential compensation by additional connexin isoforms. CONCLUSIONS: Together, our data suggest that a distinct pericyte lineage emerges alongside vasculogenesis and directly communicates with the nascent endothelium via Cx43 during early vessel formation. Cx43/Gja1 loss in pericyte/mural cell progenitors can induce embryonic vessel dysmorphogenesis, but alternate connexin isoforms may be able to compensate. These data provide insight that may reshape the current framework of vascular development and may also inform tissue revascularization/vascularization strategies.
BACKGROUND: Vascular pericytes stabilize blood vessels and contribute to their maturation, while playing other key roles in microvascular function. Nevertheless, relatively little is known about involvement of their precursors in the earliest stages of vascular development, specifically during vasculogenesis. METHODS: We combined high-power, time-lapse imaging with transcriptional profiling of emerging pericytes and endothelial cells in reporter mouse and cell lines. We also analyzed conditional transgenic animals deficient in Cx43/Gja1 (connexin 43/gap junction alpha-1) expression within Ng2+ cells. RESULTS: A subset of Ng2-DsRed+ cells, likely pericyte/mural cell precursors, arose alongside endothelial cell differentiation and organization and physically engaged vasculogenic endothelium in vivo and in vitro. We found no overlap between this population of differentiating pericyte/mural progenitors and other lineages including hemangiogenic and neuronal/glial cell types. We also observed cell-cell coupling and identified Cx43-based gap junctions contributing to pericyte-endothelial cell precursor communication during vascular assembly. Genetic loss of Cx43/Gja1 in Ng2+ pericyte progenitors compromised embryonic blood vessel formation in a subset of animals, while surviving mutants displayed little-to-no vessel abnormalities, suggesting a resilience to Cx43/Gja1 loss in Ng2+ cells or potential compensation by additional connexin isoforms. CONCLUSIONS: Together, our data suggest that a distinct pericyte lineage emerges alongside vasculogenesis and directly communicates with the nascent endothelium via Cx43 during early vessel formation. Cx43/Gja1 loss in pericyte/mural cell progenitors can induce embryonic vessel dysmorphogenesis, but alternate connexin isoforms may be able to compensate. These data provide insight that may reshape the current framework of vascular development and may also inform tissue revascularization/vascularization strategies.
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