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Grant Course Oral

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Meghan Sauve

on 19 October 2012

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Transcript of Grant Course Oral

The role of tumor necrosis factor alpha in control of microvascular tone in a mouse model of type 2 diabetes Meghan Sauvé
PSL1066H CIHR Grant Proposal Vascular complications of diabetes Diabetes-induced alteration of the structural and functional properties of resistance arteries within the microvascular circulation ultimately contributes the trophic and degenerative symptoms that clinically emerge as part of disease progression. Resistance arteries display autoregulation: myogenically responding to changes in pressure to tightly control blood flow, tissue perfusion and blood pressure in the whole organism. Project hypothesis: We hypothesize that diabetes will alter the myogenic response in the mouse, and that TNFalpha, through S1P signaling, is the primary molecule regulating perturbations of myogenic tone. 1: Myogenic tone is augmented in diabetic mice, as a result of high circulating levels of blood glucose, and upon normalization of glucose via anti-diabetic therapy, tone will be comparable to normoglycemic controls. 3. The link between diabetes and increased myogenic tone is TNFalpha, produced due to high glucose, through its ability to activate Sphk1 and thereby the S1P2 signaling pathway. 2: The observed increase in the myogenic response in mice with diabetes is mediated by activation of Sphk1, and therefore S1P, acting upon its receptor S1P2. Remaining experimental goals
Glucose:
Diabetes treatment with metformin

S1P signaling:
S1R2 receptor knockout mice
RTPCR for Sphk1 and S1P2 in WT mice

TNFalpha involvement:
Western blot analyses and immunostaining for TNFalpha
Plasma TNFalpha

Systemic relevance/effect on TPR:
Measurement of CO (Echocardiography) and blood pressure

Relevance in other vascular beds:
Posterior cerebral arteries Aim 1: Myogenic tone is significantly increased in diabetic mice. Aim 2b Hypothesis: We hypothesize that modulation of S1P activity through its receptor, S1P2, is involved in the observed enhancement of myogenic tone in diabetic mouse mesenteric arteries. Aim 3: Enhancement of myogenic tone in diabetic vessels is mediated by TNFalpha. High glucose TNFalpha Stem cells EDHF MMPs IL-6, IL-8, iNOS, MCP-1, ICAM, VCAM, E-selectin eNOS Caspase NADPH oxidase increased endothelial cell apoptosis decreased NO availability increased oxidative stress via O2- increased vascular inflammation increased vascular remodelling decreased vasorelaxation reduced vascular repair Mechanisms for altered myogenic tone in diabetes GK rats: non-obese, neither hyperlipidemic nor hypertensive, glucose intolerant and insulin resistant
augmented myogenic tone
downregulation of ET-1/ETA pathway (remodeling), glucose Obese Zucker rat: insulin resistant, moderate hypertension
augmented myogenic tone
oxidative stress through peroxynitrite db/db mouse: hypertensive
augmented myogenic tone
CoX-2-dependent release of prostaglandins (PGH2/TxA2) and PKC STZ rats: increased glucose levels, decreased insulin production
augmented myogenic tone
Endothelium-dependent release of NO, leading to membrane depolarization of the VSMC, potentially resulting in Ca2+ entry and thus vasoconstriction STZ rat:
reduced myogenic tone, partially normalized with exogenous insulin
vasodilatory prostaglandins Sachidanandam, et al. 2009 Frisbee, et al. 2002 Aim 1: Diabetic animals have increased blood glucose. These data suggest that manipulation of TNF alters the myogenic response in diabetic mouse mesenteric arteries through the sphingosine-1-phosphate 2 receptor signaling pathway. The proposed molecular mechanisms could lead to novel therapeutic strategies that alleviate the detrimental microvascular effects of diabetes and present an opportunity for curative intervention for patients living with type 1 and type 2 diabetes. Acknowledgements Program Committee
Steffen-Sebastian Bolz
Peter Backx
Pat Brubaker
Adria Giacca
Mansoor Husain Bolz Lab Members
Mostafa El Beheiry
Sonya Hui
Jeff Kroetsch
Andrew Levy
Darcy Lidington
Firhan Malik
Kenji Nagi
Anja Meissner
Julia Voigtländer-Bolz Responses to reviewers Potential confounding factors from increased fat deposition.
- TNFalpha as an Sphk1 activator
- HFD mice have comparable myogenic and constrictory responses to lean control mice

Non-specific effects of metformin treatment.
- Pleiotropic effects, including antihypertensive, anti-inflammatory, vasculoprotective, and lipid lowering properties

Compensatory myogenic mechanisms in knockout mice.
- Unpublished data from our laboratory demonstrates that there is no effect of genetic ablation of S1P2, Sphk1 and TNFalpha on baseline myogenic tone
- a conditional (Tamoxifen-inducible), smooth muscle cell-specific (SMMHC promoter) TNFalpha knockout mouse model will be employed (breeding is presently underway) Aim 2a Hypothesis: We hypothesize that increased myogenic tone in mice with diabetes is mediated by activation of Sphk1. TNFalpha
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