An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis

Christopher T.A. Lewis, Keith S. Mascall, Heather M. Wilson, Fiona Murray, Keith M. Kerr, George Gibson, Keith Buchan, Gary R. Small, Graeme F. Nixon* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
3 Downloads (Pure)

Abstract

Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFLt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.
Original languageEnglish
Pages (from-to)25-37
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume174
Early online date4 Nov 2022
DOIs
Publication statusPublished - Jan 2023

Bibliographical note

Acknowledgements
The authors would like to acknowledge the NHS Grampian Biorepository for their support and assistance with all immunohistochemistry.

Sources of funding
This work was generously funded by the British Heart Foundation, UK (FS/17/28/32807) and Grampian NHS Endowments.

Keywords

  • Aortic valve stenosis
  • Hypoxia
  • Neovascularisation
  • Angiogenesis

Fingerprint

Dive into the research topics of 'An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis'. Together they form a unique fingerprint.

Cite this