Unorthodox angiogenesis in skeletal muscle

Objective: The morphological pattern of angiogenesis occurring in mature, d ifferentiated skeletal muscle in response to chronically increased muscle b lood flow, muscle stretch or repetitious muscle contractions was examined t o determine (a) whether capillary neoformation follows the generally accept ed temporal paradigm, and (b) how the growth pattern is influenced by mecha nical stimuli. Methods: Adult rats were treated for a maximum of 14 days ei ther with the vasodilator prazosin, to elevate skeletal muscle blood flow, or underwent surgical removal of one ankle flexor. to induce compensatory o verload in the remaining muscles. or had muscles chronically stimulated by implanted electrodes. Extensor digitorum longus and/or extensor hallucis pr oprius muscles were removed at intervals and processed for electron microsc opy. A systematic examination of capillaries and their ultrastructure: char acterised the sequence of morphological changes indicative of angiogenesis, i.e., basement membrane disruption, endothelial cell (EC) sprouting and pr oliferation [immunogold labelling after bromodeoxyuridine (BrdU) incorporat ion]. Results: Capillary growth in response to increased blood flow occurre d by luminal division without sprouting or basement membrane (BM) breakage. In stretched muscles, EC proliferation and abluminal sprouting gave rise t o new capillaries, with BM loss only at sprout tips. These distinct mechani sms appear to be additive as in chronically stimulated muscles (increased b lood flow with repetitive stretch and shortening during muscle contractions ) both forms of capillary growth occurred. Endothelial cell numbers per cap illary profile, mitotic EC nuclei, and BrdU labelling confirmed cell prolif eration prior to overt angiogenesis. Conclusions: Physiological angiogenesi s within adult skeletal muscle progresses by mechanisms that do not readily conform to the consensus view of capillary growth, derived mainly from obs ervations made during development, pathological vessel growth, or from in v itro systems. The temporal and spatial pattern of growth is determined by t he polarity of the mechanical stimulus, i.e., by intra-luminal (increased s hear stress) or abluminal (external stretch) stimuli. (C) 2001 Elsevier Sci ence B.V. All rights reserved.