Ageing tissue is characterised by an alteration in mechanical properties, with tissues becoming increasingly fragile, stiff and less resilient over time. This can lead to a loss of function in tissues which undergo a high degree of stretch and recoil, such as the skin, blood vessels and lungs. These changes are attributed to remodelling of the dermal extra cellular matrix (ECM) proteins which endow tissue with its mechanical properties. Principally the fibrillar collagens provide tensile strength, complemented by the elastic fibres which confer resilience and allow tissues to recoil following deformation. Intriguingly, at the time of menopause, which sees the cessation of the majority of circulating estrogen, skin undergoes accelerated ageing. This strongly suggests a direct link between circulating estrogen and youthful skin. Using an ovariectomised (Ovx) mouse model of human menopause the link between ageing, estrogen deficiency and the dermal ECM proteins was explored. Mechanical testing revealed a significant reduction in the tensile strength, Young's modulus and stress relaxation time of estrogen deprived tissue, indicating postmenopausal skin would be weaker, more lax and less able to withstand sustained force. Corresponding histological analysis highlighted the elastic fibres are dramatically reduced by estrogen deprivation with seemingly little effects on the fibrillar collagen abundance or alignment. Direct comparison between Ovx and age, reveals age affects mechanical properties in a completely opposing way, with aged tissue higher in tensile strength, Young's modulus and stress relaxation time compared to control and Ovx. Proteomic analysis by mass spectrometry confirmed elastic fibres to be highly sensitive to estrogen levels. Additionally small leucine rich proteoglycans (SLRP's) were also significantly reduced by estrogen deficiency, which could affect collagen fibrillogenesis and leave tissue weaker and more susceptible to damage. Despite the opposing effects on mechanical properties, ageing and estrogen deficiency had comparable effects on ECM abundance, suggesting the amount of ECM is not a predictor of mechanical properties; however disparity may be in part due to increased advanced glycation end product crosslinking. Further investigation suggests the mechanism for elastic fibre degradation may be via significant subcutaneous adipose hypertrophy and/or increased gelatinase activity. Both estrogen replacement and stimulation of estrogen receptor alpha with the agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (PPT) were found to prevent elastic fibre degradation and adipose hypertrophy. Additionally these treatments were also found to induce key elastic fibre proteins in both the mouse model and cultured human dermal fibroblasts. A deeper understanding of estrogen mediated ECM remodelling offers opportunities for targeted pharmacological intervention to slow the effects of menopause and ageing.
|Date of Award||1 Aug 2017|
- The University of Manchester
|Supervisor||Michael Sherratt (Supervisor), Brian Derby (Supervisor) & Matthew Hardman (Supervisor)|
- Estrogen Elastic fibres Extracellular Matrix Skin ageing