Angiogenesis, the formation of new blood vessels, requires communication between endothelial and mural cells to maintain vascular integrity. Mural cells include pericytes, which cover small blood vessels, and vascular smooth muscle cells (VSMCs), which cover large vessels and arterioles. Pericyte can differentiate into VSMCs, but the mechanisms underlying mural cell development are unclear. Here, Tatsuo Furuyama and colleagues identify the role of macrophages in the pericyte-to-VSMC transition in the mouse retinal vasculature. The authors first look at how endothelial-derived FOXO1, a transcription factor, affects mural cell distribution. Using an endothelial-specific constitutively active Foxo1 mouse line, the authors observe accumulation of TGFβ1-producing macrophages and pericytes in the angiogenic front of developing retinas and ectopic smooth muscle cell distribution. Next, from in vitro and in vivo experiments, the authors find that SEMA3C derived from endothelial cells is transcriptionally regulated by FOXO1 and act as macrophage attractant, promoting pericyte-to-VSMC differentiation. Furthermore, by depleting macrophages with a drug and blocking SEMA3C activity with a neutralising antibody, the authors confirm that both macrophages and SEMA3C are crucial for pericyte transition to VSMCs. Overall, the findings suggest that macrophages are recruited to the endothelial angiogenesis front and promote TGFβ-dependent pericyte-to-VSMC transition in the developing retinal vasculature.
