The vascular disrupting agent combretastatin impairs splitting and sprouting forms of physiological angiogenesis.

Objective:  Vascular-disrupting agents like combretastatin (CA-4-P), used to attenuate tumour blood flow in vivo, exert anti-mitotic and anti-migratory effects on endothelial cells in vitro. We tested whether anti-vascular or anti-angiogenic effects of CA-4-P are evident with physiological angiogenesis in skeletal muscle (EDL) due to sustained hyperaemia (intraluminal splitting) and chronic muscle overload (abluminal sprouting). Methods:  CA-4-P was given i.v. (25 mg(.) kg(-1) on alternate days for 14 d) to mice subjected to angiogenic stimuli (prazosin or synergist extirpation). The responses of femoral artery blood flow as well as capillarity, capillary ultrastructure, and levels of Rho GTPase were measured. Results:  Blood flow was unaffected in the sprouting angiotype, but decreased in the splitting angiotype, by CA-4-P. In contrast, CA-4-P attenuated the capillarity increase in both models, associated with reduced lamellipodia and filopodia formation. Muscle overload, but not hyperaemia was accompanied by an increase in Rho GTPase with CA-4-P. Conclusion:  CA-4-P impaired the angiogenic response in both experimental models. This inhibitory effect was associated with a lower increase in femoral blood flow in splitting, while sprouting angiogenesis was accompanied by higher Rho activity consistent with interruption of actin polymerisation. Thus, CA-4-P may exert context-dependent anti-vascular and anti-angiogenic effects in vivo under physiological conditions.