Abstract
AbstractBlood vessel networks expand in a 2-step process that begins with vessel sprouting and is followed by vessel anastomosis. Vessel sprouting is induced by chemotactic gradients of the vascular endothelial growth factor (VEGF), which stimulates tip cell protrusion. Yet it is not known which factors promote the fusion of neighboring tip cells to add new circuits to the existing vessel network. By combining the analysis of mouse mutants defective in macrophage development or VEGF signaling with live imaging in zebrafish, we now show that macrophages promote tip cell fusion downstream of VEGF-mediated tip cell induction. Macrophages therefore play a hitherto unidentified and unexpected role as vascular fusion cells. Moreover, we show that there are striking molecular similarities between the pro-angiogenic tissue macrophages essential for vascular development and those that promote the angiogenic switch in cancer, including the expression of the cell-surface proteins TIE2 and NRP1. Our findings suggest that tissue macrophages are a target for antiangiogenic therapies, but that they could equally well be exploited to stimulate tissue vascularization in ischemic disease.
Highlights
Blood vessels are essential for tissue homeostasis in all vertebrates, and new vessel growth, termed neo-angiogenesis, is a critical process in wound repair to counter tissue ischemia
We demonstrate here that yolk sac– derived macrophages expressing TIE2 and NRP1 comprise the major population of tissue macrophages at the time of brain vascularization, and that they interact with endothelial tip cells to promote vascular anastomosis downstream of VEGFmediated tip cell formation and sprout induction
Macrophages originate from bone marrow–resident hematopoietic stem cells via circulating intermediates known as monocytes
Summary
Blood vessels are essential for tissue homeostasis in all vertebrates, and new vessel growth, termed neo-angiogenesis, is a critical process in wound repair to counter tissue ischemia. We previously elucidated the mechanism by which alternative splice forms of the vascular endothelial growth factor (VEGF) cooperate to promote blood vessel growth.[1,2] This work led to the current model of angiogenesis, in which blood vessel endothelium specializes into tip and stalk cells to promote vascular network expansion by sprouting growth. Cooperating with VEGF, notch-delta signaling controls the balance of tip versus stalk cell specialization.[3] Even though much progress has been made in elucidating the mechanism of vascular sprout induction and guidance, a fundamental yet unanswered problem is which mechanism promotes the fusion of nascent vessel sprouts to add new circuits to the existing plexus
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