The role of perivascular adipose tissue in vascular function: how hyperglycaemia and adiposity affect vascular control

Saleem, Mohammad Shahzad (2019) The role of perivascular adipose tissue in vascular function: how hyperglycaemia and adiposity affect vascular control. PhD thesis, University of Nottingham.

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Abstract

Hyperglycaemia associated with diabetes may have detrimental effects on vascular function. Diabetes may be accompanied by obesity which can potentially compound impaired vascular function by altering the physiological state of adipose tissue. Perivascular adipose tissue (PVAT), the exterior covering layer of most blood vessels, is receiving interest as a paracrine modulator of vascular function. Most conventional pharmacological studies dissect off the adherent adipose tissue and so this aspect of vascular control is often neglected. The present study aimed to investigate the effects of hyperglycaemia and PVAT on control of the porcine coronary artery (PCA).

In vitro studies were carried out, using PCAs obtained from the abattoir, in organ-bath set ups. Exposure of PCAs to acute hyperglycaemia (22 mM) caused a significant contractile response, which was similar to that caused by the osmotic control (mannitol) and which was attenuated by superoxide dismutase. Superoxide production was detected in the buffer solution incubated with PCAs during hyperglycaemia. These findings suggest that acute hyperglycaemia increased PCA contractility by inducing oxidative stress, which involved superoxide production. Osmotic stress may possibly have contributed to hyperglycaemia-induced vasoconstriction, which needs to be investigated in future work.

The relaxant responses of PCAs to the NO donor (SNP) in the presence of PVAT showed significant potentiation, compared to the vessels without PVAT. Inhibition of NOS in PCAs (denuded of endothelium) led to a contractile response, which was significantly greater in the presence of PVAT. The Griess reaction detected the presence of nitrite in buffer solutions incubated with PVAT. Moreover, the expression of eNOS was identified in PVAT using Western blotting. These data indicate that the PVAT of PCAs released the relaxant factor NO.

Exposure of cleaned PCAs to PVAT significantly increased the basal tone of the vessels which was significantly attenuated in the presence of a thromboxane A2 (TXA2) receptor antagonist. In addition, PVAT enhanced the contractile responses to 4-AP-induced inhibition of vascular voltage-activated K+ channels (Kv) channels. This enhancement was attenuated following TXA2 receptor inhibition. These findings point to the release of TXA2 from PVAT, which had a contractile effect by augmenting the closure of Kv channels of PCAs.

In addition, isometric tension studies showed that the maximal endothelium-dependent vasorelaxation to cumulative bradykinin was significantly inhibited in the presence of exogenous angiotensin II and PVAT. The later effect was ameliorated by inhibition of the angiotensin II, type 1 (AT1) receptor. ELISA showed the presence of angiotensin II in PVAT. However, Western blotting carried out to detect the expression of ACE1 (which converts angiotensin I to angiotensin II) in PVAT showed non-specific bands and was inconclusive. Angiotensin II may have been released from PVAT which interfered with the endothelium-dependent relaxation responses.

In conclusion, the present study has shown that hyperglycaemia influenced the function of PCAs by causing a contractile response possibly mediated by induction of oxidative stress. Moreover, PVAT impacted on function of the adjacent vascular smooth muscle plausibly via release of the relaxant factor NO and the contractile factor TXA2. Finally, PVAT-derived angiotensin II may have inhibited the function of endothelium of PCAs in a paracrine manner. Future studies in porcine and human coronary arteries will help to further investigate this area.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Chan, Susan
Randall, Michael
Keywords: Perivascular adipose tissue; Hyperglycaemia; Adiposity; Vascular function
Subjects: Q Science > QP Physiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 56817
Depositing User: Saleem, Mohammad
Date Deposited: 09 Aug 2019 13:38
Last Modified: 07 May 2020 10:46
URI: http://eprints.nottingham.ac.uk/id/eprint/56817

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