Abstract
Insulin and inflammatory cytokines may be involved in equine laminitis, which might be associated with digital vascular dysfunction. This study determined the effects of TNF-α and insulin on the endothelial-dependent relaxant responses of equine digital blood vessels and on equine digital vein endothelial cell (EDVEC) cGMP production. Isolated rings of equine digital arteries (EDAs) and veins (EDVs) were obtained and EDVECs were cultured from horses euthanized at an abattoir. The effect of incubation with TNF-α (10ng/ml) and/or insulin (1,000μIU/ml) for 1.5h or overnight under hyperoxic and hypoxic conditions on carbachol (endothelium-dependent) induced relaxation was assessed. The time course and concentration dependency of the effect of TNF-α and the effect of insulin (1,000μIU/ml) on EDVEC cGMP production was determined. Incubation of EDAs overnight with TNF-α under hypoxic conditions resulted in endothelial-dependent vascular dysfunction. EDVs produced a more variable response. TNF-α increased EDVEC cGMP formation in a time- and concentration-dependent manner. Insulin had no significant effects. There is a mismatch between the results obtained from isolated vessel rings and cultured endothelial cells suggesting TNF-α may reduce the biological effect of NO by reducing its bioavailability rather than its formation, leading to endothelial cell dysregulation.
Highlights
Laminitis is a common and painful condition of the horse characterised by failure of the attachment of the epidermal cells of the epidermal laminae to the underlying basement membrane of the dermal laminae [1]
Insulin activates both the phosphatidylinositol (PI3) kinase pathway resulting in stimulation of endothelial nitric oxide synthase and vasodilation and the mitogen activated protein (MAP) kinase pathway resulting in enhanced production of endothelin-1 (ET-1) and vasoconstriction [14]
There was no significant effect of incubation with 10 ng/ml TNF- and/or 1000 μIU/ml insulin for 11⁄2 hours, under hyperoxic or hypoxic conditions, on carbachol induced relaxation of isolated rings of equine digital arteries (EDAs; Figure 1) or equine digital veins (EDVs; Figure 2)
Summary
Laminitis is a common and painful condition of the horse characterised by failure of the attachment of the epidermal cells of the epidermal laminae to the underlying basement membrane of the dermal laminae [1]. Tumour necrosis factor- (TNF-α) is a pro-inflammatory cytokine secreted by leukocytes and various other cells, including the non fat cells in adipose tissue of obese individuals, which plays an important role in HMS [13]. This cytokine is implicated in vascular and endothelial dysfunction, mainly through promotion of redox signalling to inhibit flux through the PI-3 kinase pathway distal to the insulin receptor or via activation of serine kinases [16, 17]
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