Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels

Stryder M. Meadows, Peter J. Fletcher, Carlos Moran, Ke Xu, Gera Neufeld, Sophie Chauvet, Fanny Mann, Paul A Krieg, Ondine Cleaver

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Rationale: Positive signals, such as vascular endothelial growth factor, direct endothelial cells (ECs) to specific locations during blood vessel formation. Less is known about repulsive signal contribution to shaping vessels. Recently, "neuronal guidance cues" have been shown to influence EC behavior, particularly in directing sprouting angiogenesis by repelling ECs. However, their role during de novo blood vessel formation remains unexplored. Objective: To identify signals that guide and pattern the first mammalian blood vessels. Methods and Results: Using genetic mouse models, we show that blood vessels are sculpted through the generation of stereotyped avascular zones by EC-repulsive cues. We demonstrate that Semaphorin3E (Sema3E) is a key factor that shapes the paired dorsal aortae in mouse, as sema3E embryos develop an abnormally branched aortic plexus with a markedly narrowed avascular midline. In vitro cultures and avian grafting experiments show strong repulsion of ECs by Sema3E-expressing cells. We further identify the mouse notochord as a rich source of multiple redundant neuronal guidance cues. Mouse embryos that lack notochords fail to form cohesive aortic vessels because of loss of the avascular midline, yet maintain lateral avascular zones. We demonstrate that lateral avascular zones are directly generated by the lateral plate mesoderm, a critical source of Sema3E. Conclusions: These findings demonstrate that Sema3E-generated avascular zones are critical regulators of mammalian cardiovascular patterning and are the first to identify a repulsive role for the lateral plate mesoderm. Integration of multiple, and in some cases redundant, repulsive cues from various tissues is critical to patterning the first embryonic blood vessels.

Original languageEnglish (US)
Pages (from-to)34-36
Number of pages3
JournalCirculation Research
Volume110
Issue number1
DOIs
StatePublished - Jan 6 2012

Fingerprint

Cues
Blood Vessels
Endothelial Cells
Notochord
Mesoderm
Embryonic Structures
Genetic Models
Vascular Endothelial Growth Factor A
Aorta
Axon Guidance

Keywords

  • endothelial
  • lateral plate mesoderm
  • neuronal guidance cues
  • notochord
  • Sema3E

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Meadows, S. M., Fletcher, P. J., Moran, C., Xu, K., Neufeld, G., Chauvet, S., ... Cleaver, O. (2012). Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels. Circulation Research, 110(1), 34-36. https://doi.org/10.1161/CIRCRESAHA.111.249847

Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels. / Meadows, Stryder M.; Fletcher, Peter J.; Moran, Carlos; Xu, Ke; Neufeld, Gera; Chauvet, Sophie; Mann, Fanny; Krieg, Paul A; Cleaver, Ondine.

In: Circulation Research, Vol. 110, No. 1, 06.01.2012, p. 34-36.

Research output: Contribution to journalArticle

Meadows, SM, Fletcher, PJ, Moran, C, Xu, K, Neufeld, G, Chauvet, S, Mann, F, Krieg, PA & Cleaver, O 2012, 'Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels', Circulation Research, vol. 110, no. 1, pp. 34-36. https://doi.org/10.1161/CIRCRESAHA.111.249847
Meadows, Stryder M. ; Fletcher, Peter J. ; Moran, Carlos ; Xu, Ke ; Neufeld, Gera ; Chauvet, Sophie ; Mann, Fanny ; Krieg, Paul A ; Cleaver, Ondine. / Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels. In: Circulation Research. 2012 ; Vol. 110, No. 1. pp. 34-36.
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