Angiogenesis – may the force be with you!

Angiogenesis is defined as the formation of new blood vessels from pre-existing vessels, in particular capillaries, and is controlled by a complex balance between pro- and anti-angiogenic factors. It plays a crucial role during embryonic and fetal development, reparative processes such as wound healing, physiological challenges such as pregnancy, and following changes in metabolic demand, e.g. during exercise training of striated muscle. More than 70 diseases may have an angiogenic component to the pathology, with either excessive or insufficient capillary supply, although the vast majority of research to date has examined tumour angiogenesis and thus concentrated on angiogenesis inhibition. This $4 billion, largely industry-driven effort has sought chemical signals that may be blocked by pharmaceutical interventions. The ‘magic bullet’ approach can lead to quite remarkable effects in animal models, but has so far produced disappointing results in humans, where it is now recognised that a combination of therapeutic modalities is required. But what drives capillary growth in adaptive tissue remodelling?

Physiological angiogenesis, exemplified by the response to muscle activity, appears more driven by mechanical signals. Following in the footsteps of Olga Hudlická's pioneering work, we have started to elucidate the differential signalling involved in alternative ways of growing capillaries in skeletal muscle of rats and mice (Egginton, 2009). This involved developing approaches to isolate, as best as is possible with in vivo models, the mechanical signals relevant to muscle activity: increased shear stress (by vasodilators) and passive stretch of muscle fibres (by overload). Changes in endothelial structure and expression profiles for various growth factors, proteases, adhesion molecules and endogenous inhibitors revealed a differential role for NO production and matrix metalloproteinase (MMP) activity in splitting and sprouting forms of angiogenesis, respectively. These appear to be driven by mechanotransduction of haemodynamic forces by the endothelium, modulated by metabolic demands of the host tissue, with the angiogenesis promoter vascular endothelial growth factor (VEGF) playing a central role (Fig. 1).

Figure 1.

Chemotransduction of signals arising from increased muscle activity by the endothelium may lead to increased capillarisation by two distinct processes, sprouting and splitting forms of angiogenesis, as does mechanotransduction of altered haemodynamic forces. In addition to differential responses there are common elements, typified by VEGF signalling.

The Copenhagen School was founded a hundred years ago by Johannes Lindhard and August Krogh to study various aspects of the body's response to exercise, which they reported in great detail and precise terms. Much of our understanding of human muscle physiology comes from the invasive studies conducted there over many years, repeatedly directing attention to hitherto unexplored avenues of enquiry, including one of the first papers showing that increased capillary supply was an adaptive response of muscle to endurance training in humans (Andersen & Henriksson, 1977). It is fitting, therefore, that the latest paper from that very productive heritage to be published in The Journal of Physiology continues this enlightened tradition (Høier et al. 2010).

Ylva Hellsten's group have adopted a different approach to isolating the signals involved in driving adaptive angiogenesis associated with muscle activity. They and others provide a good example of translation from animal (Gavin & Wagner, 2001) to human (Gustafsson et al. 2002) studies in showing the dynamic response to short bouts of intense exercise involved an angiogenic response. The key finding was that VEGF may be produced by myocytes. This prompted them to determine whether passive muscle training (i.e. movement with little or no EMG activity) may act as a stimulus for release of pro-angiogenic cytokines using a combination of muscle biopsies, interstitial fluid dialysis and cell culture.

Training without working may sound like a couch-potato's dream, but this innovative approach demonstrated that both capillary density and the number of capillaries around a fibre were significantly enhanced after 2 weeks. Importantly, increased capillarisation occurred only in the trained leg, confirming a positive angiogenic effect of passive movement in these subjects. Interestingly, the contralateral leg is usually not refractory to change. In both animals and human studies of increased muscle activity, blood flow may increase in the contralateral limb due to shifting balance. However, this does not occur during passive movement, suggesting that blood-borne factors may be restricted to the ipsilateral limb, likely candidates being cytokines such as IL-6 or IL-8. The passive training model may therefore prove helpful for understanding which physiological factors are important for capillary growth in skeletal muscle.

The novel observation that in habitually active, healthy individuals passive training led to alterations in angiogenic readouts and induced increased capillarisation is quite remarkable and clearly has therapeutic potential. It may be useful with inactive elderly individuals, peripheral arterial disease patients with exercise claudication, and for patients with enforced inactivity (e.g. knee injuries), to improve or maintain limb capillarisation.