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Angiogenesis

, Volume 22, Issue 1, pp 167–183 | Cite as

Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation

  • Jordan Darden
  • Laura Beth Payne
  • Huaning Zhao
  • John C. ChappellEmail author
Original Paper
  • 400 Downloads

Abstract

Pericyte investment into new blood vessels is essential for vascular development such that mis-regulation within this phase of vessel formation can contribute to numerous pathologies including arteriovenous and cerebrovascular malformations. It is critical therefore to illuminate how angiogenic signaling pathways intersect to regulate pericyte migration and investment. Here, we disrupted vascular endothelial growth factor-A (VEGF-A) signaling in ex vivo and in vitro models of sprouting angiogenesis, and found pericyte coverage to be compromised during VEGF-A perturbations. Pericytes had little to no expression of VEGF receptors, suggesting VEGF-A signaling defects affect endothelial cells directly but pericytes indirectly. Live imaging of ex vivo angiogenesis in mouse embryonic skin revealed limited pericyte migration during exposure to exogenous VEGF-A. During VEGF-A gain-of-function conditions, pericytes and endothelial cells displayed abnormal transcriptional changes within the platelet-derived growth factor-B (PDGF-B) and Notch pathways. To further test potential crosstalk between these pathways in pericytes, we stimulated embryonic pericytes with Notch ligands Delta-like 4 (Dll4) and Jagged-1 (Jag1) and found induction of Notch pathway activity but no changes in PDGF Receptor-β (Pdgfrβ) expression. In contrast, PDGFRβ protein levels decreased with mis-regulated VEGF-A activity, observed in the effects on full-length PDGFRβ and a truncated PDGFRβ isoform generated by proteolytic cleavage or potentially by mRNA splicing. Overall, these observations support a model in which, during the initial stages of vascular development, pericyte distribution and coverage are indirectly affected by endothelial cell VEGF-A signaling and the downstream regulation of PDGF-B-PDGFRβ dynamics, without substantial involvement of pericyte Notch signaling during these early stages.

Keywords

Pericyte VEGF-A Angiogenesis Mouse embryonic stem cells Development 

Abbreviations

Ng2

Neural glial antigen-2

VEGF

Vascular endothelial growth factor

ESC

Embryonic stem cell

PDGF

Platelet-derived growth factor

Notes

Acknowledgements

We thank the Chappell Lab for critical and extensive discussions of the primary data.

Funding

This study was funded by the National Institutes of Health (R00HL105779 and R56HL133826 to JCC), National Heart, Lung, and Blood Institute (Grant Nos. HL105779, HL133826), Division of Chemical, Bioengineering, Environmental, and Transport Systems (Grant No. 1752339).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

10456_2018_9648_MOESM1_ESM.docx (39 kb)
Online Resource 1—Supplemental Materials and Methods (DOCX 39 KB)
10456_2018_9648_MOESM2_ESM.pdf (18.2 mb)
Online Resource 2—Supplemental Figure 1 (PDF 18639 KB)
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Online Resource 3—Supplemental Figure 2 (PDF 202 KB)
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Online Resource 4—Supplemental Figure 3 (PDF 5029 KB)
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Online Resource 5—Supplemental Figure 4 (PDF 171 KB)
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Online Resource 6—Supplemental Figure 5 (PDF 152 KB)
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Online Resource 7—Supplemental Figure 6 (PDF 246 KB)
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Supplementary Movie 1 (AVI 5406 KB)
10456_2018_9648_MOESM9_ESM.avi (5.6 mb)
Supplementary Movie 2 (AVI 5722 KB)

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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Center for Heart and Regenerative MedicineVirginia Tech Carilion Research InstituteRoanokeUSA
  2. 2.Graduate Program in Translational Biology, Medicine, and HealthVirginia Polytechnic Institute and State UniversityBlacksburgUSA
  3. 3.Department of Biomedical Engineering and MechanicsVirginia Polytechnic Institute and State UniversityBlacksburgUSA
  4. 4.Department of Basic Science EducationVirginia Tech Carilion School of MedicineRoanokeUSA

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