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Exploring the role of the lipid phosphatase SHIP2 in systemic metabolism and vascular biology

Patel, Peysh Acyuta (2018) Exploring the role of the lipid phosphatase SHIP2 in systemic metabolism and vascular biology. PhD thesis, University of Leeds.

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Abstract

Metabolic dysregulation in the form of insulin-resistant type 2 diabetes mellitus leads to premature death and disability, primarily as a consequence of vascular dysfunction. This relates to accelerated atherosclerosis, diminished vascular repair and dysfunctional angiogenesis. A number of complementary systems exist to regulate insulin sensitivity, and maladaptive activation of these may contribute to pathophysiology. SHIP2 is a lipid phosphatase which catalyses the conversion of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) to phosphatidylinositol (3,4)-biphosphate PI(3,4)P2 in insulin responsive tissues. It therefore suppresses activation of signalling cascades downstream of phosphoinositide-3-kinase (PI3K), consistent with a negative role of SHIP2 in insulin signalling. However, the effects of SHIP2 manipulation on metabolic and vascular function have not been clearly elucidated. We hypothesised that SHIP2 inhibition would have favourable effects on insulin-mediated glucose lowering, vascular repair and angiogenesis. Studies were primarily performed on mice with germline endothelium-specific (ECSHIP2Δ/+), or whole body inducible (SHIP2iΔ/+) SHIP2 catalytic domain haploinsufficiency, using a Cre-lox approach. A complementary model was explored in human umbilical vein endothelial cells (HUVECs) using shRNA-mediated knockdown or pharmacological inhibition of SHIP2. ECSHIP2Δ/+ mice exhibited impaired vascular formation in the developing postnatal retinas, associated with increased endothelial PI3K/AKT signalling and Nox2-mediated vascular oxidative stress. Alterations in these signalling intermediates and superoxide generation were recapitulated in HUVECs. This was associated with defects in endothelial cell migration and polarisation, although no differences in proliferative capacity were observed. SHIP2iΔ/+ mice had enhanced whole body glucose disposal and insulin sensitivity. They exhibited skeletal muscle hypervascularity in the context of hindlimb ischaemia, which was manifest as increased vessel thickness without alterations in vessel abundance. No differences in re-endothelialisation after denuding arterial injury were apparent in this model. In conclusion, SHIP2 activity appears critical in preservation of metabolic and vascular homeostasis during health and disease. Elements of this role may relate to suppression of oxidative stress that arises from unrestrained PI3K-Nox2 signalling. Further exploration to extend our mechanistic understanding is required, but the findings of this project suggest that caution is warranted before SHIP2 inhibition can be considered as a viable therapeutic strategy in clinical contexts.

Item Type: Thesis (PhD)
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Keywords: SHIP2, vascular biology, metabolism
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds)
Depositing User: Dr P A Patel
Date Deposited: 13 Nov 2018 15:46
Last Modified: 13 Nov 2018 15:46
URI: http://etheses.whiterose.ac.uk/id/eprint/22013

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