Hif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish

Macrophages are known to interact with endothelial cells during developmental and pathological angiogenesis but the molecular mechanisms modulating these interactions remain unclear. Here, we show a role for the Hif-1 alpha transcription factor in this cellular communication. We generated hif-1aa;hif-1ab double mutants in zebrafish, hereafter referred to as hif-1 alpha mutants, and find that they exhibit impaired macrophage mobilization from the aorta-gonad-mesonephros (AGM) region as well as angiogenic defects and defective vascular repair. Importantly, macrophage ablation is sufficient to recapitulate the vascular phenotypes observed in hif-1 alpha mutants, revealing for the first time a macrophage-dependent angiogenic process during development. Further substantiating our observations of vascular repair, we find that most macrophages closely associated with ruptured blood vessels are Tnf alpha-positive, a key feature of classically activated macrophages. Altogether, our data provide genetic evidence that Hif-1 alpha regulates interactions between macrophages and endothelial cells starting with the mobilization of macrophages from the AGM.