Differential cell-matrix responses in hypoxia-stimulated aortic versus mitral valves

J R Soc Interface. 2016 Dec;13(125):20160449. doi: 10.1098/rsif.2016.0449.


Tissue oxygenation often plays a significant role in disease and is an essential design consideration for tissue engineering. Here, oxygen diffusion profiles of porcine aortic and mitral valve leaflets were determined using an oxygen diffusion chamber in conjunction with computational models. Results from these studies revealed the differences between aortic and mitral valve leaflet diffusion profiles and suggested that diffusion alone was insufficient for normal oxygen delivery in mitral valves. During fibrotic valve disease, leaflet thickening due to abnormal extracellular matrix is likely to reduce regional oxygen availability. To assess the impact of low oxygen levels on valve behaviour, whole leaflet organ cultures were created to induce leaflet hypoxia. These studies revealed a loss of layer stratification and elevated levels of hypoxia inducible factor 1-alpha in both aortic and mitral valve hypoxic groups. Mitral valves also exhibited altered expression of angiogenic factors in response to low oxygen environments when compared with normoxic groups. Hypoxia affected aortic and mitral valves differently, and mitral valves appeared to show a stenotic, rheumatic phenotype accompanied by significant cell death. These results indicate that hypoxia could be a factor in mid to late valve disease progression, especially with the reduction in chondromodulin-1 expression shown by hypoxic mitral valves.

Keywords: angiogenesis; calcification; extracellular matrix; heart valve; oxygen diffusion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Aorta / pathology
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix / pathology
  • Fibrosis
  • Heart Valve Diseases / metabolism*
  • Heart Valve Diseases / pathology
  • Mitral Valve / metabolism*
  • Mitral Valve / pathology
  • Myocardial Ischemia / metabolism*
  • Myocardial Ischemia / pathology
  • Swine