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41 Transcriptional profiling reveals a requirement for phosphodiesterase 10A during flow-induced vessel remodelling in the chick embryo
  1. E C Hoggar1,
  2. M Placzek1,
  3. T J Chico2
  1. 1MRC Centre for Biomedical and Developmental Genetics, The University of Sheffield, Sheffield, UK
  2. 2NIHR Cardiovascular Biomedical Research Unit, Sheffield Teaching Hospitals, Sheffield, UK

Abstract

Objective The biological response of blood vessels to blood flow is central to atherosclerosis and collateral vessel development. We therefore characterised the transcriptional response of the chick extra-embryonic vasculature during flow-induced remodelling in an attempt to identify potential drivers of this process.

Methods and Results Left vitelline artery ligation induced remodelling of the contralateral vasculature, with collateral vessels supplying the ligated territory. Collaterals arose by enlargement of pre-existing vessels, and expressed the arterial marker Neuropilin-1, while downregulating the venous marker Neuropilin-2. The collateral network demonstrated active remodelling, with an early peak in collateral number at 12-h post ligation, followed by pruning and selection of a more efficient haemodynamic configuration of less, larger vessels. We characterised global transcriptional changes 4 and 12-h post ligation and found that developing collaterals displayed a distinct gene expression profile. Among 164 differentially expressed protein coding mRNAs, phosphodiesterase 10A (PDE10A) was highly upregulated at the site of flow-induced remodelling at 4 h. Local application of the PDE10A inhibitor Papaverine Hydrochloride had no effect on normal vessel diameter or development but significantly impaired collateral development.

Conclusions Flow-induced vascular remodelling in the chick induces dynamic changes in vessel architecture, associated with marked transcriptional changes distinct from normal vessel patterning. PDE10A is upregulated during flow induced remodelling and pharmacologic inhibition significantly impairs this process.

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