An adequate blood supply is clearly required for optimal tissue function; vascular remodelling is usually induced by altered metabolic demand. Key to this regulation is the process of angiogenesis, involving formation of new vessels from existing ones. Despite developing what is thought to be a pro-angiogenic environment associated with tissue hypoxia there is little evidence for capillary growth as a consequence of chronic limb ischaemia, possibly due to the inability to develop an adequate luminal shear stress associated with increased blood flow (Hudlickç et al. 1992). We reasoned that application of chronic overload, which induces angiogenesis in the absence of altered blood flow (Egginton et al. 1998), to ischaemic muscle offers a potentially beneficial angiotherapy.
Male Wistar rats underwent unilateral overload of the m. extensor digitorum longus (EDL) by extirpation of the agonist m. tibialis anterior, with or without the imposition of muscle ischaemia induced by ipsilateral ligation of the common iliac artery. Surgery was performed under Xylanyn and Ketalar anaesthesia (I.P.) with post-operative antibiotics (S.C.), consistent with UK legislation. Six weeks later, when animals were humanely killed, overloaded muscles (O) had undergone hypertrophy of 39 % and 52 % (ANOVA, P < 0.01) relative to contralateral (CL) and control muscles (Control), respectively (P < 0.01). This response was not prevented by the combination of overload and ischaemia (O/I), where relative hypertrophy was 24 % (CL) and 35 % (Control), respectively (P < 0.01). Muscle fibre cross-sectional area paralleled changes in muscle mass, with means of 1872 ± 80, 2253 ± 90 and 2292 ± 67 mm2 (mean ± S.E.M., n = 6) for Control, O and O/I, respectively (both P < 0.01 vs. Control). Capillary to fibre ratio (C:F) was significantly increased in overloaded (2.70 ± 0.07) compared with both contralateral (1.77 ± 0.04) and control (1.61 ± 0.05) muscles (P < 0.001). Similarly, C:F was higher in overloaded plus ischaemic muscle (2.65 ± 0.11) compared with contralateral (1.40 ± 0.03) and control values (P < 0.01). In both O and O/I muscle groups, the highest increase in C:F and capillary density was found in the region of EDL where fibre size was largest. In contrast, the degree of hypertrophy of fibres was lowest in the same region for both groups. These data suggest that the microvascular deficit evident in chronic muscle ischaemia may be alleviated by angiogenesis which is induced by mechanical stimuli via muscle overload. This could facilitate release of endogenous angiogenic factors, thereby avoiding difficulties inherent in exogenous growth factor therapy.