Whether chronic hypoxia causes angiogenesis in skeletal muscle is controversial. Male Wistar rats, 5--6 wk of age, were kept at constant 12% O(2) for 3 wk, and frozen sections of their postural soleus (SOL), phasic extensor digitorum longus (EDL), and tibialis anterior (TA) muscles were compared with those of normoxic controls. Capillary supply increased in SOL muscles [capillary-to-fiber ratio (C/F) = 2.55 +/- 0.09 hypoxia vs. 2.17 +/- 0.06 normoxia; capillary density (CD) = 942 +/- 14 hypoxia vs. 832 +/- 20 mm(-2) normoxia, P < 0.01] but not in EDL muscles (C/F = 1.44 +/- 0.04 hypoxia vs. 1.42 +/- 0.04 normoxia; CD = 876 +/- 52 hypoxia vs. 896 +/- 24 mm(-2) normoxia). The predominantly glycolytic cortex of TA muscles showed higher C/F after hypoxia (1.79 +/- 0.09 vs. 1.53 +/- 0.05 normoxia, P < 0.05), whereas the mainly oxidative TA core with smaller fibers showed no change in capillarity. The region of the SOL muscle with large-sized (mean fiber area 2,843 +/- 128 microm(2)) oxidative fibers (90% type I) had a higher C/F (by 30%) and CD (by 25%), whereas there was no angiogenesis in the region with sparse (76%) and smaller-sized (2,200 +/- 85 microm(2)) type I fibers. Thus systemic hypoxia differentially induces angiogenesis between and within hindlimb skeletal muscles, with fiber size contributing either directly (via a metabolic stimulus) or indirectly (via a mechanical stimulus) to the process.
Angiogenesis during normal muscle growth does not maintain CD, but with similar heterogeneity of capillary spacing it preserves the potential for adequate intramuscular oxygenation.
Chronic systemic hypoxia results in a series of changes in the respiratory and cardiovascular systems that help preserve tissue oxygenation. In particular, ventilation is increased and erythropoiesis is induced (Ou et al. 1992). Chronic tissue hypoxaemia is thought to provide a stimulus for growth of capillaries (Hudlicka et al. 1992), although whether systemic hypoxia induces angiogenesis in skeletal muscle has been controversial. Thus, chronic hypoxia was shown to increase capillary density, but it was argued that this reflected a decrease in muscle fibre size rather than true angiogenesis (Banchero et al. 1976; Adair et al. 1990). Accordingly, it was reported that exposure to 10 % O 2 for 5 weeks, or 12 % O 2 for 12 weeks did not change capillary to fibre ratio (C:F) in diaphragm or leg muscles of the rat (Snyder et al. 1985; Bigard et al. 1991). By contrast, in a recent study on the rat we showed that chronic systemic hypoxia (at 12 % O 2) for up to 3 weeks did cause angiogenesis, as indicated by an increase in C:F, in diaphragm and soleus muscles, but not in extensor digitorum longus or tibialis anterior muscles (Deveci et al. 2001). We also provided evidence that there was a relationship between fibre size and angiogenesis, such that the increase in C:F was greater in regions of muscle where the fibres were of larger cross-sectional area (Deveci et al. 2001). However, the experiments performed by other groups used a longer period of chronic hypoxia (≥ 6 weeks) than we had used. Given that many adaptations to hypoxia are transient, the aim of the present study was to establish whether 6 weeks of chronic systemic hypoxia induced further angiogenesis between or within muscles. METHODS All experiments were performed in accordance with the UK Animals (Scientific Procedures Act) 1986. Male Wistar rats (5-6 weeks old) were held for 6 weeks in an hypoxic chamber regulated at 12 % O 2 with CO 2 removal (Thomas & Marshall, 1995). Experimental groups were matched for age and mass: initial body mass (BM) was 178 ± 4 g and final BM, 356 ± 7 g (mean ± ..., n = 6); normoxic controls were of similar BM (357 ± 4 g, n = 6). Animals were killed by pentobarbitone overdose
We tested the hypothesis that alterations in arterioles in locomotor skeletal muscles in rats with myocardial infarction (MI), but before development of congestive heart failure (CHF), precede structural and functional changes commonly observed in limb muscle in association with CHF. Resting diameters of third- (A3) and fourth-order arterioles (A4) in extensor digitorum longus (EDL) muscle were significantly smaller in rats with nonfailing small and medium-sized MI compared with control animals. Dilation of A4 in response to 10−4 M adenosine was significantly attenuated in both groups ( P < 0.05), whereas dilation of A3 was unaltered. Microvessels from both groups of infarcted rats constricted to all doses of acetylcholine (10−9, 10−8, and 10−7 M) and showed a significantly exaggerated vasoconstrictor response to norepinephrine (10−9, 10−8, and 10−7 M) compared with microvessels in control rats ( P < 0.05). Peak isometric tension of combined tibialis anterior and EDL muscles and muscle fatigue (final/peak tension × 100), measured during 5-min isometric supramaximal twitch contractions at 4 Hz, were similar in control and MI rats (218 ± 7 vs. 213 ± 15 g/g muscle and 52 ± 1 vs. 51 ± 9%, respectively; n = 5 for both). There was also no difference with respect to the proportion of oxidative fibers or capillary-to-fiber ratios. Our results indicate that, in rats with left ventricular dysfunction but without failure, decreased diameter and perturbations in reactivity of small arterioles precede alterations in skeletal muscle performance often seen at a later date in association with CHF. These findings are consistent with the notion of aberrant endothelial and smooth muscle function and may contribute to the maintenance of blood pressure after MI but before CHF.
We have demonstrated that the fluorescent microsphere technique can be used in small mammals for accurate determination of regional blood flows. In particular we have shown that 100% recovery of trapped microspheres is possible, that tissue digestion can be completed in a shorter time than previously reported, and the error-prone filtration method can be replaced with one of sedimentation. The method gave very good agreement among different fluorescent labels (r2 > 0.99) and low variability among tissues (mean coefficient of variation = 0.06). Simultaneous injection of radiolabelled and fluorescent microspheres established comparability between these methods (r2 = 0.96) for blood flows measured at rest, during vasodilator-induced hypotension, and in muscle hyperaemia during indirect electrical stimulation. Fluorescent microspheres can therefore replace radioactive microspheres for the determination of blood flow with advantages in both safety and cost, without loss of sensitivity.
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