Vascular Complications of Obesity

Endothelial dysfunction
Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium, such as impaired vasodilation, angiogenesis and barrier function, inflammatory activation and increased plasma levels of endothelial products, all of which are generally associated with cardiovascular disease. In the human clinical context, endothelial dysfunction is regarded as an important and early factor in the pathogenesis of atherothrombosis and vascular complications of diabetes (types 1 and 2) and is associated with a number of traditional risk factors including hypercholesterolaemia, smoking, hypertension, diabetes mellitus and insulin resistance and, more recently, obesity. In the equine clinical context, endothelial dysfunction appears to play a role in the pathogenesis of laminitis.

A key feature of endothelial dysfunction is the inability of arteries and arterioles to dilate appropriately in response to stimuli. This limits the delivery of nutrients and hormones to the distal tissues. Two mechanisms play an important role. The first dominant mechanism is a decreased bioavailability of the potent vasodilator nitric oxide (NO). The bioavailability of NO is determined by a balance of NO production by endothelial nitric oxide synthase (eNOS) and reduction of active NO by quenching of NO by reactive oxygen intermediates (ROIs), particularly the superoxide anion. The generation of ROIs also affects other functions of the endothelium. Either directly via ROI or via a reduction of NO, the nuclear factor kappa-B (NF-κB) pathway is activated with, subsequently, the activation of numerous genes involved in inflammation. In particular, the cell adhesion molecules VCAM, ICAM-1 and E-selectin have drawn much attention as they represent major receptors controlling the influx of monocytes and other inflammatory cells into the arterial wall. The second mechanism is increased synthesis of endothelin-1 (ET-1) by activated endothelial cells which induces vasoconstriction. [...]