title: The vascular-disrupting agent combretastatin impairs splitting and sprouting forms of physiological angiogenesis.
abstract: OBJECTIVE
  Vascular-disrupting agents like combretastatin (CA-4-P), used to attenuate tumor 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 hyperemia (intraluminal splitting) and chronic muscle overload (abluminal sprouting).
  
  
  METHODS
  CA-4-P was given i.v. (25 mg/kg on alternate days for 14 days) 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 hyperemia, was accompanied by an increase in Rho GTPase with CA-4-P.
  
  
  CONCLUSIONS
  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, whereas sprouting angiogenesis was accompanied by higher Rho activity consistent with the interruption of actin polymerization. Thus, CA-4-P may exert context-dependent anti-vascular and anti-angiogenic effects in vivo under physiological conditions.
authors.affiliation: Department of Physiology, University of Birmingham Medical School, Birmingham, UK.
authors.forename: Arif
authors.initials: A
authors.lastname: Hussain
authors.forename: Manuel
authors.initials: M
authors.lastname: Steimle
authors.forename: Hans
authors.initials: H
authors.lastname: Hoppeler
authors.forename: Oliver
authors.initials: O
authors.lastname: Baum
authors.forename: Stuart
authors.initials: S
authors.lastname: Egginton
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001632:Bibenzyls / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D005263:Femoral Artery / Q000378:metabolism; D006940:Hyperemia / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D050257:Tubulin Modulators / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D001632:Bibenzyls; D050257:Tubulin Modulators; C040105:combretastatin; D020741:rho GTP-Binding Proteins