Physiological angiogenesis can take place by capillary sprouting, longitudinal splitting of vessels or by intussusceptive growth. Other than during development and in female reproductive organs, it occurs in cardiac and skeletal muscle exposed to endurance training. Although knowledge of growth patterns is somewhat limited, capillary sprouting has been reported in trained animal hearts linked with endothelial proliferation (White et al. 1998), while capillary elongation, and possibly splitting, occur in trained skeletal muscle (Appell, 1984). We hypothesised that the pattern of growth is determined by angiogenic stimuli acting from the abluminal capillary surface (stretch, upregulation of growth factors in the tissue) leading to sprouting and/or intussusceptive growth, or from the luminal surface (shear stress, cicumferential wall stress, release of humoral/growth factors) resulting in splitting, and that growth can occur with or without endothelial cell proliferation.

Persistent increase in blood flow induced by vasodilator treatment results in capillary growth in both heart and skeletal muscle. In the latter it occurred by splitting, with minimal proliferation, and was associated with a transient increase in the level of endothelial cell stimulating angiogenic factor (ESAF) and a transient elevation of capillaries expressing VEGF protein. Stretch of cardiac myocytes by long-term administration of the inotrope dobutamine or by bradycardial pacing, both of which increase stroke work but not blood flow, led to proliferative capillary growth, with increased levels of ESAF, but not FGF-2. Stretch of hindlimb skeletal muscle by overload following agonist muscle removal resulted in capillary growth by sprouting, preceded by endothelial proliferation, and accompanied by increased level of ESAF, but not FGF-2 and a transient increase in number of capillaries expressing VEGF. After chronic muscle stimulation, both sprouting and splitting of capillaries occurred with endothelial proliferation, while increased VEGF and ESAF followed (see Brown et al. 2001).

Capillaries exposed to increased luminal flow by vasodilators had higher shear stress than in control muscles, and growth occurred without breakage of the basement membrane (BM) or metalloproteinase (MMP-2) enhancement. With muscle stretch, where blood flow was unchanged but capillaries were mechanically stressed abluminally, sprouting growth occurred with BM breakage at sprout tips and increased MMP-2 expression (Goldstein et al. 2001). In stimulated muscles, capillaries experienced both higher shear stress and mechanical distortion during contractions with the result that endothelial proliferation preceded BM breakage and increased MMP-2 expression (Haas et al. 2000).

Thus the pattern of angiogenesis is indeed dependent on the type and direction of mechanical stimulus with capillary splitting, limited proliferation and no change in metalloproteinase activity occurring in response to luminal stimuli while abluminal stimuli (stretch) result in capilary sprouting facilitated by increased MMP expression.

The work was supported by the MRC, Wellcome Trust and British Heart Foundation.

Appell, H.J. (1984). Progress Appl. Microcirc. 5, 15-29.

Brown, M.D., Milkiewicz, M. & Hudlicka, O. (2001). J. Physiol. 536.P, 12S.

Goldstein, J., Milkiewicz, M., Hansen-Smith, F., Brown, M.D., Hudlicka, O. & Haas, T.L. (2001). FASEB. 15, A53.

Haas, T.L., Milkiewicz, M., Davis, S.J., Zhou, A.-L., Egginton, S., Brown, M.D., Madri, J.A. & Hudlicka, O. (2000). Am. J. Physiol. 279, H1540-1547.

White, F.C., Bloor, C.M., McKirnan, M.D. & Caroll, S.M. (1998). J. Appl. Physiol. 85, 1160-1168.