Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

Calum Wilson*, Xun Zhang, Mathew D. Lee, Margaret MacDonald, Helen R. Heathcote, Nasser M.N. Alorfi, Charlotte Buckley, Sharron Dolan, John G. McCarron

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Surprisingly, while impaired endothelial function occurs in the earliest stages of obesity, the mechanisms linking weight gain and endothelial dysfunction are poorly-defined. To study obesity-related vascular function without the complications associated with diabetes, we induced a state of prediabetic obesity in rats. Small artery diameter recordings revealed decreased endothelial-dependent vasodilator responses in obese animals, similar to patient studies. Endothelial control of vascular tone was dependent on increases in intracellular calcium and nitric oxide production. Single-photon calcium imaging of large populations of endothelial cells revealed a linear relationship between vascular relaxation and network-level calcium responses. The relationship was unaltered in obesity. However, endothelial calcium responses, arising from subpopulations of agonist-sensitive cells and communicated across the cell network, were reduced. This impairment of population-wide endothelial calcium signaling arose, not from altered communication among endothelial cells, but from increased clustering of a decreased number of agonist-sensitive cells. This study demonstrates that impaired vascular function may arise from deficient endothelial cell heterogeneity and collective network activity, and provides a novel mechanism for understanding compromised endothelial function in disease.
Original languageEnglish
Article number154340
Number of pages10
JournalMetabolism
Volume111
Early online date10 Aug 2020
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

  • vascular function
  • obesity
  • endothelium

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