Abstract

Morphogenesis of the postnatal developing vasculature involves two essential processes: angiogenesis, which is responsible for the formation and expansion of the capillary bed, and arteriogenesis, which remodels a part of the capillary bed into the arterial vasculature. A rich pool of studies over the past two decades suggested that the vascular endothelial growth factor A (VEGF-A, VEGF hereafter unless otherwise specified), the primary inducer of angiogenesis, also promotes arteriogenesis. However, this fails to explain the spatiotemporal segregation of angiogenesis and arteriogenesis during postnatal vascular morphogenesis. It is also unclear how the same molecule, a proliferation-inducing growth factor, can be responsible for two very different processes, one of which (angiogenesis) requires active cell proliferation and the other (arteriogenesis) requires growth arrest. Interestingly, arterial specification in VEGF loss-of-function (LOF) animal models has not been examined. Here, we report that physiological doses of VEGF do not induce arterial fate in capillary endothelial cells, instead serving as a physiological brake to slow down fluid shear stress (FSS)-driven capillary-to-arterial fate transition. Studies in four different mouse models with fully or partially disrupted VEGF signaling show impaired angiogenesis but preservation of arteriogenesis, accompanied by ectopic arterialization particularly in the artery-associated capillary bed. The interplay of VEGF and FSS, two essential environmental cues guiding vascular morphogenesis, converges on the mechanosensitive transcription factor Sox17 that regulates expression of key arterial fate genes. We conclude that while angiogenic signaling promotes vascular expansion and protects the capillary bed from premature and ectopic arterialization driven by blood flow, cessation of angiogenic signaling is required to permit FSS-driven arteriogenesis. These findings establish a new paradigm of VEGF-FSS crosstalk coordinating angiogenesis, arteriogenesis and capillary maintenance during vascular morphogenesis.