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13 Flow Induced Vessel Remodelling in the Chicken Embryo is Associated with A Specific Gene Expression Profile
  1. EC Hoggar1,
  2. M Placzek1,
  3. T J Chico2
  1. 1MRC Centre for Biomedical and Developmental Genetics, The University of Sheffield, Sheffield, United Kingdom
  2. 2NIHR Cardiovascular Biomedical Research Unit, Sheffield Teaching Hospitals, Sheffield, United Kingdom

Abstract

Collateral vessel development occurs by remodelling of pre-existing endothelial communications between occluded and neighbouring vascular territories to restore blood flow following occlusion of a large conducting artery. We have identified the genes involved in blood vessel remodelling in the chick embryo model of collateral vessel formation. In ovo ligation of the vitelline artery of E3 chick embryos occluded blood flow to the right side of the extra-embryonic vascular network. Collaterals arose by enlargement of pre-existing vessels and demonstrated active remodelling, peaking in number at 12h post ligation, followed by selection of a more efficient haemodynamic configuration of fewer, larger vessels over 48h. We characterised the global transcriptional changes at 4 and 12h post ligation and found 164 differentially expressed genes, unique to developing collateral vessels and therefore suggested to be driven by shear stress. Phosphodiesterase 10A (PDE10A) was highly up-regulated at 4h post-ligation. Local application of the PDE10A inhibitor Papaverine Hydrochloride had no effect on normal vessel diameter (ctrl 466±34µm, Papaverine [20uM] 600±90µm) but significantly impaired collateral vessel formation at 24h post-ligation (ctrl 109±9µm, Papaverine [20uM] 49±5 µm P<0.0001). Time course micrographs revealed significantly reduced collateral development from 6h post-ligation. In vitro proliferation assays using explanted collateral vessels, showed that flow-sensitised endothelial cells treated with papaverine, had a significantly lower proliferation index than controls at 12h post-ligation (ctrl 8.5%±0.5, Papaverine [20uM]) 2.5%±1.5 P=0.04). We conclude that developing collateral vessels demonstrate a unique gene expression profile. PDE10A is up-regulated during flow induced remodelling and pharmacologic inhibition significantly impairs this process.

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