Chronic vasodilator treatment intensifies levels of shear stress in capillary beds, stimulating a specific form of angiogenesis termed longitudinal splitting, while sustained muscle overload induces the more familiar sprouting form of capillary growth (Egginton, 2001). Similar findings are observed in both rats and mice. These differently directed mechanical forces (luminal and abluminal, respectively) expand the capillary bed to a similar extent over a similar time-course, but by different growth processes characterised by unique features in structure, gene expression and protein complement (Williams et al. 2006). Elevated capillary shear stress is transduced into an angiogenic response irrespective of the vasodilator mechanism employed, with the essential involvement of endothelial nitric oxide synthase. Surprisingly, the rate of capillary growth thus recruited is largely mirrored by the rate of capillary regression on withdrawal of vasodilator treatment, involving reciprocal changes in VEGF and eNOS, but low levels of endothelial mitosis or apoptosis. In vitro responses of endothelial cells (EC) to elevated shear stress leads to differential regulation of a number of genes involved in the control of angiogenesis. Interestingly, shear appears to regulate molecules that modify VEGF effects, rather than VEGF per se. EC motility is increased by VEGF, although shear appears to inhibit EC migration when confluent layers are wounded in parallel to flow axis. Capillary growth following overload is critically dependent on matrix metalloprotease activity and, as with shear-dependent growth, the presence of elevated VEGF levels. Angiogenesis does not appear to be dependent on a threshold stimulus, as seen by the differential in capillarity and EC proliferation in response to graded muscle overload. However, the response is mediated by a threshold, rather than a graded response in VEGF or Flk-1, suggesting the degree of angiogenesis is likely controlled by interactions among pro-angiogenic stimuli. There was little evidence for synergistic potentiation when applied in combination with either high flow (pharmacological dilatation) or low flow (surgical ischaemia), suggesting that feedback control limits the extent of angiogenesis in skeletal muscle.