Heterogeneous metabolic response of endothelial cells from different vascular beds to experimental hyperglycaemia and metformin (original) (raw)

McAleese, C. ORCID: https://orcid.org/0000-0003-2756-4941, Joudah, G., Salt, I.P. ORCID: https://orcid.org/0000-0003-0055-3724, Petrie, J.R. ORCID: https://orcid.org/0000-0002-4894-9819, Leiper, J.M. ORCID: https://orcid.org/0000-0003-4656-519X and Dowsett, Laura B. ORCID: https://orcid.org/0000-0002-3356-8183(2025) Heterogeneous metabolic response of endothelial cells from different vascular beds to experimental hyperglycaemia and metformin.Journal of Physiology, (doi: 10.1113/JP288006) (PMID:39998029) (Early Online Publication)

Abstract

Endothelial cells (ECs) are highly glycolytic, with mitochondria primarily serving a signalling function. Metabolic disruptions are early contributors to endothelial dysfunction, a primary feature of diabetic vascular complications, such as retinopathy, impaired wound healing and cerebral small vessel disease. The degree to which metabolism varies amongst such different vascular beds is unknown. Mitochondrial function was therefore characterised in human aortic, dermal, retinal and cerebral ECs in vitro, aiming to determine whether basal metabolism influences the response and susceptibility of vascular beds experimental hyperglycaemia (HG). Furthermore, the potential of metformin to maintain endothelial function independent of glycaemic control was assessed. Using a Seahorse analyser, metabolic function of human primary ECs from different vascular beds was compared under basal conditions, as well as HG and metformin treatment. ECs differed significantly in respiratory profile and glycolytic function. For example aortic ECs were preferentially aerobic, whereas dermal ECs were glycolytic. HG significantly lowered mitochondrial network area but elicited modest effects upon respiratory function at the same time as influencing glycolytic function in a manner that was possibly conditional upon basal utilisation. Metformin inhibited basal respiratory function at the same time as significantly enhancing glycolysis in retinal and brain ECs. These data suggest that EC responses to HG and metformin are influenced by the basal metabolic profile, highlighting the potential of targeting EC metabolism to preserve function in a diabetic condition. A nuanced approach is needed to address diabetic vascular complications and endothelial metabolic health in diabetes, both in the investigation of pathophysiology and in prospective therapeutics.

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Funder and Project Information

BHF 4Yr PhD Studentship Award 2020

Rhian Touyz

FS/4yPhD/F/20/34127

SCMH - Cardiovascular & Metabolic Health

Asymmetric dimethylarginine signalling via the calcium sensing receptor in the vascular and metabolic complications of type 2 diabetes

Laura Dowsett

PG/21/10531

SCMH - Cardiovascular & Metabolic Health

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