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 flt-1 differentially affects the branching complexity of vascular networks in tissues despite similar effects on endothelial sprouting. We selectively ablated flt-1 in the post-natal retina and found that maximum induction of flt-1 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 flt-1 revealed that sprouting endothelial cells flanked by flt-1−/− 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 flt-1-regulated angiogenic molecular and cellular mechanisms to yield optimal vessel patterning for a given tissue.
Highlights
Sufficient blood flow is vital for tissue and organ homeostasis
For potent pro-angiogenic cues, such as Vascular Endothelial Growth Factor-A (VEGF-A), negative feedback regulation is critical for maintaining vessel growth within a productive range; how these feedback mechanisms integrate into overall blood vessel formation, is not well-understood
In this study, using conditional genetic recombination tools to manipulate the expression of the decoy VEGF-A receptor Flt-1 in developing mouse retina, we analyzed how Flt-1 can regulate endothelial cell sprouting behaviors non cell-autonomously, as previously described [8,20,21,25,26,28,29,31], yet elicit differential vessel patterning outcomes [32]
Summary
Sufficient blood flow is vital for tissue and organ homeostasis. Blood vessel growth and remodeling must be tightly regulated to achieve appropriate structural patterns and densities.Underdeveloped or malformed vascular networks lead to insufficient blood flow and inadequate nutrient delivery [1,2], while vessel overgrowth is detrimental and results in poor tissue oxygenation [3,4,5,6]. Sufficient blood flow is vital for tissue and organ homeostasis. Blood vessel growth and remodeling must be tightly regulated to achieve appropriate structural patterns and densities. Negative feedback mechanisms within pro-angiogenic signaling pathways are critical for maintaining developing vessel networks within a range of sufficient but not excessive growth and for ensuring that vascular networks form in the appropriate locations. Endothelial cell responses to Vascular Endothelial Growth Factor-A (VEGF-A), among other angiogenic cues [2,7], require precise coordination, achieved, in part, through feedback regulation of VEGF-A receptor expression and activity [8,9,10]. The VEGF-A activation of endothelial cells can be modulated via a decreased expression of the pro-angiogenic VEGF-A receptor Flk-1
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