The role of hypoxia on interstitial mitral valve cells

Mitral valve disease is a multifactorial process. The valve is a complex structure that contains an amalgam of extracellular proteins, cellular components, nerves and blood vessels. It is predicted that some of the central portions of the valve leaflets could exist under hypoxic conditions. Hypoxia could play a role in initiating the structural changes in the valve that lead to dysfunction of the valve. It is known to cause the up-regulation of hypoxia-induced factor (HIF) that can regulate the differentiation of cells, the production of extracellular matrix (ECM) and expression of matrix remodelling enzymes, all of which are characteristic changes seen in one or more forms of the disease. This study aimed to investigate the effect of hypoxia on the basic behaviour and phenotypic profile of mitral valve interstitial cells (MVICs), and their functional response to produce and control the ECM components. The expression of HIF-1α and its role in mediating the effects induced by hypoxia were also investigated, and also the characteristics of blood vessels in the mitral valve leaflet in porcine as well as normal and diseased human valves. MVICs incubated under hypoxia remained viable and continued to grow, while retaining their morphology and phenotype. On the other hand, severe hypoxia resulted in reduced production of the ECM components sulphated glycosaminoglycan (sGAG) and collagen, while it induced matrix metabolism through up-regulating the gene expression of matrix metalloproteases and their tissue inhibitors. Human rheumatic valves had more evident expression of HIF-1α compared with normal or myxomatous degeneration valves. Porcine MVICs (pMVICs) expressed HIF-1α under hypoxia. Stimulating HIF-1α chemically causes a reduction in the amount of GAG produced, similar to the effect observed under severe hypoxia. The study also confirmed the presence of vascular supply to the normal mitral valve leaflets and showed that there was increased vascularisation in rheumatic valves, while there was a loss of vessels in myxomatous degenerative ones. In conclusion, normal mitral valve leaflets are vascular structures of variable pattern. Diseased valves are associated with changes in leaflet vascularity either by neovascularisation in rheumatic disease, or by loss of vascularisation in myxomatous degeneration. Hypoxia affects the production of certain ECM proteins and remodelling enzymes by MVICs. These effects appear to be mediated by the induction of HIF-1α. This study highlights an important process and mechanism in heart valve in health and disease and helps improve the understanding of its complex biology. This could have future implications on the treatment of valve disease and the future applications in heart valve tissue engineering.Open Acces