Increasing age is the single biggest independent risk factor for cardiovascular disease, which is in turn the leading cause of morbidity and mortality worldwide. Ageing is associated with hypertension and metabolic changes which all increase the risk of the development of cardiovascular disease. In young, healthy individuals, perivascular adipose tissue (PVAT) secretes factors that can influence vascular contractility, exerting a net anti-contractile effect against numerous vasoconstrictors including the thromboxane A2 mimetic U46619 and alpha1-adrenoceptor phenylephrine. Whilst it is known that dysfunction in PVAT can contribute to obesity-related hypertension, little is known whether similar dysfunction occurs with ageing. In young Wistar rats, wire myography and pharmacological studies showed that the anti-contractile effect of PVAT in the presence of U46619 is dependent on both PVAT-derived nitric oxide and prostaglandins, whereas the anti-contractile effect in the presence of phenylephrine is nitric oxide independent. This finding was supported by Western blot experiments that showed increased phosphorylation of endothelial nitric oxide synthase (eNOS) in PVAT following U46619 incubation, but not phenylephrine. In the Wistar rat model of ageing used, wire myograph studies revealed that the PVAT anti-contractile effect in the presence of phenylephrine is preserved at 24 months of age, but in in the presence of U46619 is lost. Furthermore PVAT from aged animals had a deleterious effect on endothelial function, suggesting changes in its secreted factors. These changes are accompanied by alterations in the expression and activation of key enzymes in the nitric oxide synthesis pathway within the PVAT as measured by Western blot, as well as alterations in cardiometabolic phenotype including hypertension, hyperglycaemia and insulin resistance. Taken together these findings suggest that previously unidentified age-related PVAT dysfunction may contribute to age-related hypertension and thus may provide a potential therapeutic target for future study.
|Date of Award||1 Aug 2016|
- The University of Manchester
|Supervisor||Gillian Edwards (Supervisor), Anthony Heagerty (Supervisor) & Clare Austin (Supervisor)|