Microvascular Disruption and Regeneration During Skeletal Muscle Repair
Jacobsen NL, Norton CE, Shaw RL, Cornelison DDW, Segal SS. Myofibre injury induces capillary disruption and regeneration of disorganized microvascular networks. J Physiol 2022;600(1):41-60. doi: 10.1113/JP282292.
Background: Skeletal muscle regeneration depends not only on the restoration of myofibres but also on the recovery of an intact microvascular network. While myofibre regeneration is well characterized, the processes by which capillaries and other microvessels are disrupted and reformed after injury remain poorly understood. The study investigated how microvascular structure and function change following skeletal muscle injury induced by barium chloride (BaCl2).
Hypothesis: This study hypothesized that BaCl2-induced skeletal muscle injury leads to microvascular disruption as a secondary effect of myofibre degeneration rather than direct cytotoxicity to endothelial or smooth muscle cells, and that regenerating capillary networks initially form in a disorganized manner before remodeling as myofibres mature.
Methods: The authors examined microvascular injury and regeneration in the gluteus maximus muscle of mice after BaCl2 injection. Ex vivo assays using isolated microvessels and endothelial tubes assessed membrane potential, calcium dynamics and cell viability. Confocal microscopy and three-dimensional reconstructions of resistance networks were performed using Vesselucida and Vesselucida Explorer to quantify vessel number, diameter and anastomoses.
Results: BaCl2 depolarized microvascular smooth muscle and endothelial cells and increased smooth muscle calcium but did not cause their death. In vivo, capillaries fragmented within one day post-injury, whereas arterioles and venules remained intact. Capillary networks regenerated by five days post-injury but were dilated, misaligned with myofibres and associated with increased terminal arterioles. By twenty-one days, capillary orientation and microvascular unit organization were restored to normal.
Conclusions: The findings demonstrate that capillary loss follows myofibre degeneration and that regenerating microvessels initially form disorganized, hyperdilated networks that progressively remodel into functional microvascular units as skeletal muscle regenerates.
