Microcirculation in skeletal muscle.

The role of microcirculation in skeletal muscle is to provide the supply of oxygen and various nutrients and to remove waste products of muscle metabolism. As skeletal muscles are composed of different fibre types, this review tries to elucidate the question of capillary supply and flow with respect to these. It reviews the current knowledge of structure of microcirculation and its nervous, hormonal, and local (myogenic, metabolic and endothelial) control.

Adaptation of skeletal muscle microvasculature to increased or decreased blood flow: role of shear stress, nitric oxide and vascular endothelial growth factor.

This review elucidates the roles of capillary haemodynamics, nitric oxide (NO) and vascular endothelial growth factor (VEGF) in the remodelling of skeletal muscle microcirculation in response to increased (electrical stimulation) or decreased (chronic ischaemia) blood flow. During early stages of stimulation-induced angiogenesis, up-regulation of VEGF and its receptor VEGF receptor 2 is dependent on shear stress and NO release, whereas later, involvement of NO in the expanding capillary bed appears to be VEGF/VEGF receptor 2 independent. Arteriolar growth most likely relies on mechanical wall stresses while growth factor involvement is less clear.

Vascular endothelial growth factor mRNA and protein do not change in parallel during non-inflammatory skeletal muscle ischaemia in rat.

Impaired blood flow is thought to induce a pro-angiogenic environment due to local hypoxia, yet prolonged mild ischaemia induces only modest capillary growth. We compared the expression of vascular endothelial growth factor (VEGF) mRNA and protein with capillary to fibre ratio (C: F) and muscle blood flow in extensor digitorum longus of rats that had undergone unilateral ligation of the common iliac artery. Resting blood flow during the first two weeks after ligation (3, 7 and 14 days) was decreased by approximately 60% but recovered partially after 5 weeks (36% reduction).

ICAM-1 expression and leukocyte behavior in the microcirculation of chronically ischemic rat skeletal muscles.

In muscle microcirculation, short periods of ischemia followed by reperfusion are known to upregulate leukocyte and endothelial adhesion molecules, but little is known about leukocyte adherence and ICAM-1 expression during chronic ischemia or any likely effect of muscle activity which is recommended in chronic ischemia due to peripheral arterial disease. Leukocyte rolling and stationary adhesion were observed in post-capillary venules in ischemic and contralateral rat extensor digitorum longus (EDL) muscles 3 and 7 days after unilateral ligation of the common iliac artery and in 3-day ischemic EDLs that were electrically stimulated on days 1 and 2 post-ligation (7 x 15 min per day). ICAM-1 was localized immunohistochemically to venular vessels in all muscles.

Changes in capillary shear stress in skeletal muscles exposed to long-term activity: role of nitric oxide.

Objective: The purpose of this study was to establish whether suppression of angiogenesis by nitric oxide synthase (NOS) inhibition in skeletal muscles exposed to long-term activity can be explained by changes in capillary shear stress linked to the lack of nitric oxide production.

Methods: Capillary shear stress was calculated from diameters (d) and red blood cell velocities (V(rbc)) measured at rest and after acute contractions in epi-illuminated extensor digitorum longus muscles of control rats and those in which ankle flexors had been stimulated via implanted electrodes (10 Hz, 8 h x day(-1)) for 2 or 7 days without and with inhibition of nitric oxide synthase activity by N(omega)-nitro-L-arginine (L-NNA, 3-4 mg x day(-1) in drinking water).

Results: Neither chronic electrical stimulation nor L-NNA treatment altered capillary diameters.

Nitric oxide, VEGF, and VEGFR-2: interactions in activity-induced angiogenesis in rat skeletal muscle.

Vascular endothelial growth factor (VEGF) is considered to be important in promotion of capillary growth in skeletal muscles exposed to increased activity. We studied its interactions with nitric oxide (NO) by examining the expression of endothelial NO synthase (NOS), VEGF, and VEGF receptor-2 (VEGFR-2) proteins in relation to capillary growth in rat extensor digitorum longus muscles electrically stimulated for 2, 4, or 7 days with and without NOS inhibition by N(omega)-nitro-L-arginine (L-NNA, 3 mg/day). Stimulation increased all proteins from 2 days onward, concomitantly with capillary proliferation (labeling for proliferating cell nuclear antigen).

Differential expression of Flk-1 and Flt-1 in rat skeletal muscle in response to chronic ischaemia: favourable effect of muscle activity.

To determine the involvement of vascular endothelial growth factor (VEGF) and its receptors Flk-1 and Flt-1 in capillary growth in ischaemic skeletal muscle, extensor digitorum longus muscles from hindlimbs of Sprague-Dawley rats were studied at 1, 2 and 5 week intervals after iliac artery ligation. Muscle VEGF protein levels (as determined by Western-blot analysis) increased only after 2 (60%) and 5 (80%) weeks, with more capillaries positively immunostained for VEGF than in control muscles. Ischaemia-induced angiogenesis was gradual, with capillary proliferation at 1 and 2 weeks and capillary:fibre ratio increased 20% after 5 weeks.

The effect of chronic skeletal muscle stimulation on capillary growth in the rat: are sensory nerve fibres involved?

Indirect chronic electrical stimulation of skeletal muscle activates not only efferent but also afferent nerve fibres. To investigate effects specific to this on capillary growth, one of the earliest changes, cell proliferation and capillary ultrastructure were studied in ankle flexors of rats with and without deafferentation of the stimulated side. Two weeks after preganglionic section of dorsal roots L4-L6, the peroneal nerve was stimulated (10 Hz, 8 h day(-1)) for 2 or 7 days.

Differential involvement of MMP-2 and VEGF during muscle stretch- versus shear stress-induced angiogenesis.

Capillary growth in skeletal muscle occurs via the dissimilar processes of abluminal sprouting or longitudinal splitting, which can be initiated by muscle stretch and elevated shear stress, respectively. The distinct morphological hallmarks of these types of capillary growth suggest that discrete sets of angiogenic mediators play a role in each situation. Because proteolysis and proliferation are two key steps associated with capillary growth, we tested whether differences in the regulation of matrix metalloproteinases (MMPs) or VEGF may be associated with the two types of capillary growth.