The skeletal muscle microcirculation is in full control of the delivery of nutrients and oxygen to skeletal muscle fibers. The presence of a monolayer of endothelial cells on the luminal side supports this function. The total ECL surface area in an adult human has been estimated at > 700 m2. The microvasculature contributes 99% of this with most of the ECL being present in the dense network of muscle capillaries [1]. The rationale for this distribution is that the ECL in muscle controls the transendothelial transport of nutrients, oxygen and hormones into the interstitial fluid that surrounds the muscle fibres. With multiple terminal arterioles and 20-40 capillaries serving one muscle fibre, the microvasculature is acutely and chronically managing to match energy supply to the demand of individual muscle fibers. The transport capacity depends on the available surface area. About 10% of the muscle capillaries is perfused in the resting state. The additional recruitment during exercise is large and required to ensure that the supply of blood-borne fuels and oxygen meets the high energy demand of the contracting muscle fibres.Textbooks traditionally assume that activation of the insulin signalling cascade in skeletal muscle fibres is the primary control mechanism for glucose uptake. There now is compelling evidence that the delivery of insulin and glucose to the muscle interstitium is a conditional early event in muscle glucose uptake [2]. Experiments using contrast-enhanced ultrasound to estimate the volume of blood present in the muscle microvasculature, have shown that physiological increases in insulin lead to rapid increases in the microvascular blood volume in skeletal muscle. In rats these increases occur as early as 5-10 min after the start of a physiological insulin infusion and precede both activation of the muscle insulin signalling cascade and increases in muscle glucose uptake, which are seen after 15-30 min [3]. This increase in microvascular blood volume has also been observed after ingestion of a mixed meal and during light exercise and is taken to primarily reflect the recruitment of capillaries that were not perfused before. This conclusion is supported by estimates of the permeability surface area product (PSA) for insulin and glucose in human studies. The PSA went up 2-fold during an oral glucose tolerance test and 11-fold during a physiological insulin infusion, with equal-fold increases seen for skeletal muscle glucose uptake [4]. Important information on the underlying mechanisms has come from studies in cultured endothelial cells, which identified an endothelial insulin signalling cascade, in which activation of Akt leads to ser1177 phosphorylation and activation of eNOS and therefore an increase in the production of the potent vasodilator nitric oxide (NO). In vivo NO then acts upon the smooth muscle cell layer of skeletal muscle arterioles [5] and leads to vasodilatation and recruitment of additional muscle capillaries. An important in vivo observation [3] was that pre-treatment of rats with the eNOS inhibitor L-NAME prevented the insulin induced increase in microvascular blood volume in skeletal muscle and reduced both glucose uptake and activation of the insulin signalling cascade in skeletal muscle. Other signals found to activate eNOS via ser1177 phosphorylation are fluid shear forces exerted on a cultured EC monolayer and exposure of cultured EC’s to vascular endothelial growth factor (VEGF) and may be relevant for the angiogenic effect of exercise and determine perfusion rates of skeleletal muscle during exercise [6]. Topics covered in this symposium: Anton Wagenmakers will give an introduction to explain the normal function of the endothelium of the microvasculature in skeletal muscle and the impact that impairments in insulin, VEGF and exercise shear stress induced eNOS activation are expected to have on insulin sensitivity, angiogenesis and the regulation of muscle perfusion during exercise. Michelle Keske will present her latest data on the impaired microvascular responses that are seen in obesity, ageing and other insulin resistant states. Jefferson Frisbee will report the changes seen in the spatial distribution and time responses in the microvascular perfusion of skeletal muscle in rats with the metabolic syndrome. Matthew Cocks on the basis of his latest exercise training interventions will then encourage you to adopt a more physically active lifestyle to keep the density and vasodilatory potential of your skeletal muscle as high as possible and thus prevent impaired glucose tolerance and chronic disease in later life [7]. Ed Eringa will present recent data demonstrating that perivascular adipose tissue within skeletal muscle alters vascular function and impairs insulin-induced vasodilatation in muscle of obese individuals.