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Title: Novel roles of endothelial cells and adipocytes in the vasculature : modification in disease
Author: Egner, Iris
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Perivascular adipose tissue (PVAT) and vascular endothelial cells both have important structural and functional roles in blood vessels and are the focus of this doctoral thesis. Firstly, PVAT has been rediscovered as an endocrine organ, releasing vasorelaxing substances. Secondly, the endothelial monolayer functions as an important barrier, the role of which is to restrict the transfer of molecules or even blood-borne cells between the lumen of the blood vessel and the surrounding tissue. In my main study, the presence of PVAT caused 'anti-contractile' effects, which were reversed by nitric oxide synthase (NOS) inhibition in rat mesenteric arteries and were lost in adiponectin-knockout mice. The β3 adrenoceptor agonist CL-316,243 increased PVAT-dependent anti-contractile effects and caused myocyte hyperpolarisation. Hyperpolarisation to CL-316,243 could be mimicked by the adipokine, adiponectin, and by the 5'AMP kinase (AMPK) activator, A-769662. In addition, the AMPK inhibitor, dorsomorphin, and the selective BKCa channel blocker, iberiotoxin, each blocked hyperpolarisations to CL-316,243, adiponectin and A-769662. The anti-contractile effects of CL-316,243 could also be mimicked by A-769662 but were not blocked by dorsomorphin. Moreover CL-316,243 still had anti-contractile effects in adiponectin-knockout mice. However, inhibiting the production of both NO and hydrogen peroxide reduced anti-contractile effects of CL-316,243. In obese Sprague Dawley rats both the hyperpolarising and the anti-contractile effects to CL-316,243 were impaired, while hyperpolarisation to A-769662 were unchanged. Western blots revealed that NOS, a possible downstream target of AMPK, was phosphorylated in PVAT control samples, a form which was decreased in PVAT from obese rats. These results collectively indicate that the anti-contractile and hyperpolarising effects observed following stimulation with CL-316,243 are due to activation of different PVAT-dependent pathways, both of which probably contribute to vasodilatation in blood vessels. Understanding these pathways is crucial for the development of improved treatments for obesity and hypertension. During my work at Novartis, I found that activation of sphingosine-1-receptors type 1 (S1P1) with the activator FTY720 (Fingolimod, Novartis; used in multiple sclerosis treatment) caused closure of the endothelial barrier in human umbilical vein cells. This effect could be mimicked with a recombinant peptide of nectin, an adherens junction protein. The novel S1P1 antagonists 'A1' and 'A2' (Novartis) inhibited the effect of FTY720, but not those of nectin. The discovery of nectin as a potential barrier closure modulator might contribute to the development of additional treatments for use in multiple sclerosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: myocyte hyperpolarisation ; anti-contractile effect ; rat mesenteric artery ; AMP-activated protein kinase (AMPK) ; adiponectin ; CL-316,243 ; perivacular adipose tissue (PVAT)