Background: Maternal obesity pre-programme offspring to develop obesity and associated cardiovascular disease later in life. In health, perivascular adipose tissue (PVAT) reduces vascular contractility, an effect lost in obesity and during pregnancy. However, neither the effect of obesity during pregnancy on PVAT function in the mothers nor the possible epigenetic effect in the offspring is known. This study sought to identify detrimental vascular changes in post-partum dams and their offspring resulting from maternal obesity. Methods: Six-eight week old female Sprague-Dawley rats were fed a 10% fat (control) or 45% fat diet (HFD) for 12 weeks before mating, throughout pregnancy and during lactation. Offspring received the control diet until sacrifice at 12 (12wo) or 24 (24wo) weeks of age. PVAT-denuded (with or without exogenous PVAT) and PVAT-intact mesenteric arteries from mothers and pups were mounted on a wire myograph and vascular contractility to thromboxane A2 agonist (U46619) and norepinephrine was assessed in the presence of pharmacological tools. Western blotting, immunoprecipitation and an AMPK activity assay were used to detect any changes in the PVAT environment. Results: Offspring of obese mothers were overweight, mildly hypertensive and insulin resistant. Contractions in PVAT-denuded arteries from HFD dams and their offspring were reduced by a mechanism involving increased protein O-GlcNAcylation. PVAT exerted an anti-contractile effect in vessels from control offspring and their mothers through the release of relaxant factors, which included nitric oxide (NO). The anti-contractile effect of PVAT was lost in HFD offspring due to reduced NO bioavailability and increased O-GlcNAcylation, which lead to decreased AMPK activity within PVAT. However, simultaneous AMPK activation within PVAT partially restored the anti-contractile capability in HFD offspring. Reduced NO bioavailability also lead to PVAT dysfunction in HFD mothers. Conclusions: Elevated insulin levels in the HFD offspring may lead to enhanced glucose uptake and increased protein O-GlcNAcylation, which contributes to the PVAT dysfunction in HFD offspring. The PVAT dysfunction, which is associated with reduced NO bioavailability in HFD mothers and their offspring may be the result of reduced AMPK phosphorylation of nitric oxide synthase within PVAT.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:694312 |
| Date | January 2016 |
| Creators | Zaborska, Karolina Emilia |
| Contributors | Edwards, Gillian ; Austin, Clare ; Wareing, Mark |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/consequences-of-maternal-obesity-on-vascular-contractility-and-perivascular-adipose-tissue-regulation-of-resistance-artery-tone-in-rats(120fc687-c67a-442c-b87d-92be0fa2b558).html |
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