Muscle ischaemia in rats may be relieved by overload-induced angiogenesis.

Alleviation of muscle ischaemia by improving capillary supply has proved difficult, possibly reflecting the inability to substantially increase blood flow. We reasoned that muscle overload, which induces angiogenesis in the absence of altered blood flow, may be an alternative to drug therapy. Male Wistar rats underwent unilateral ligation of the common iliac artery, with or without ipsilateral extirpation of the tibialis anterior muscle. Six weeks later ischaemic (I) extensor digitorum longus (EDL) had a 10% (P < 0.05) decrease in relative muscle mass, while overloaded muscles (O) had undergone hypertrophy of 39% and 52% relative to contralateral (CL) and control (C) muscle masses, respectively (P < 0.01). Muscle atrophy was prevented by the combination of overload and ischaemia (O/I), with hypertrophy of 24% (vs. CL) and 35% (vs. C), respectively (P < 0.01). Changes in muscle fibre cross-sectional area paralleled the changes in muscle mass, with means of 1898 +/- 59, 1531 +/- 90, 2253 +/- 155 and 2292 +/- 80 mm2 for C, I, O and O/I, respectively (P < 0.01 vs. C and I). Capillary to fibre ratio (C:F) was significantly increased in overloaded (2.58 +/- 0.09) compared to contralateral (1.78 +/- 0.04), control (1.61 +/- 0.05) and ischaemic (1.73 +/- 0.06) muscles (P < 0.001). A similar increase in C:F was seen in overloaded plus ischaemic muscle (2.59 +/- 0.07) compared to contralateral (1.40 +/- 0.01) and control or ischaemic values (P < 0.01). In both O and O/I muscle groups, C:F and capillary density (CD) increased most in the region of EDL where fibre size was largest, while hypertrophy of fibres was least in the same region for both groups. These data suggest that the microvascular deficit evident in chronic muscle ischaemia may be alleviated by angiogenesis that is induced by mechanical stimuli via chronic muscle overload.