Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling
- Authors
- Watson, O., Novodvorsky, P., Gray, C., Rothman, A.M., Lawrie, A., Gerhardt, H., Crossman, D.C., Haase, A., McMahon, K., Gering, M., van Eeden, F.J., and Chico, T.J.
- ID
- ZDB-PUB-130710-107
- Date
- 2013
- Source
- Cardiovascular research 100(2): 252-61 (Journal)
- Registered Authors
- Chico, Tim J., Gering, Martin, Gray, Caroline, van Eeden, Freek
- Keywords
- none
- MeSH Terms
-
- Animals
- Blood Circulation/physiology*
- Diacetyl/analogs & derivatives
- Diacetyl/pharmacology
- Hypoxia/physiopathology*
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/physiology*
- Membrane Proteins/genetics
- Membrane Proteins/physiology*
- Neovascularization, Physiologic*
- Receptors, Notch/physiology*
- Signal Transduction/physiology*
- Tumor Suppressor Proteins/physiology
- Vascular Endothelial Growth Factor Receptor-2/physiology
- Zebrafish/embryology
- Zebrafish Proteins/physiology
- PubMed
- 23812297 Full text @ Cardiovasc. Res.
Aims The contribution of blood flow to angiogenesis is incompletely understood. We examined the effect of blood flow on Notch signalling in the vasculature of zebrafish embryos, and whether blood flow regulates angiogenesis in zebrafish with constitutively upregulated hypoxic signalling.
Methods and Results Developing zebrafish (Danio rerio) embryos survive via diffusion in the absence of circulation induced by knockdown of cardiac troponin T2 or chemical cardiac cessation. Absence of blood flow increased vascular Notch signalling in 48h post fertilisation old embryos via upregulation of the Notch ligand dll4. Despite this, patterning of the intersegmental vessels is not affected by absent blood flow. We therefore examined homozygous vhl mutant zebrafish that have constitutively upregulated hypoxic signalling. These display excessive and aberrant angiogenesis from 72h post fertilisation, with significantly increased endothelial number, vessel diameter and length. Absence of blood flow abolished these effects, though normal vessel patterning was preserved.
Conclusions We show that blood flow suppresses vascular Notch signalling via downregulation of dll4. We also shown that blood flow is required for angiogenesis in response to hypoxic signalling but is not required for normal vessel patterning. These data indicate important differences in hypoxia-driven, versus developmental, angiogenesis.