Blood Vessel Patterning on Retinal Astrocytes Requires Endothelial Flt-1 (VEGFR-1)

Abstract

Feedback mechanisms are critical components of many pro-angiogenic signaling pathways that keep vessel growth within a functional range. The Vascular Endothelial Growth Factor-A (VEGF-A) pathway utilizes the decoy VEGF-A receptor Flt-1 to provide negative feedback regulation of VEGF-A signaling. In this study, we investigated how the genetic loss of <i>flt-1</i> differentially affects the branching complexity of vascular networks in tissues despite similar effects on endothelial sprouting. We selectively ablated <i>flt-1</i> in the post-natal retina and found that maximum induction of <i>flt-1</i> loss resulted in alterations in endothelial sprouting and filopodial extension, ultimately yielding hyper-branched networks in the absence of changes in retinal astrocyte architecture. The mosaic deletion of <i>flt-1</i> revealed that sprouting endothelial cells flanked by <i>flt-1^&minus;</i>^{/<i>&minus;</i>} regions of vasculature more extensively associated with underlying astrocytes and exhibited aberrant sprouting, independent of the tip cell genotype. Overall, our data support a model in which tissue patterning features, such as retinal astrocytes, integrate with <i>flt-1</i>-regulated angiogenic molecular and cellular mechanisms to yield optimal vessel patterning for a given tissue.