Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization

TY - JOUR

T1 - Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization

AU - Wild, Raphael

AU - Klems, Alina

AU - Takamiya, Masanari

AU - Hayashi, Yuya

AU - Strähle, Uwe

AU - Ando, Koji

AU - Mochizuki, Naoki

AU - van Impel, Andreas

AU - Schulte-Merker, Stefan

AU - Krueger, Janna

AU - Preau, Laetitia

AU - le Noble, Ferdinand

PY - 2017/1/10

Y1 - 2017/1/10

N2 - Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually, our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode.

AB - Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually, our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode.

U2 - 10.1038/ncomms13991

DO - 10.1038/ncomms13991

M3 - Journal article

C2 - 28071661

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 13991

ER -