Document Detail

VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats.
MedLine Citation:
PMID:  15471974     Owner:  NLM     Status:  MEDLINE    
Both collateral vessel enlargement (arteriogenesis) and capillary growth (angiogenesis) in skeletal muscle occur in response to exercise training. Vascular endothelial growth factor (VEGF) is implicated in both processes. Thus we examined the effect of a VEGF receptor (VEGF-R) inhibitor (ZD4190, AstraZeneca) on collateral-dependent blood flow in vivo and collateral artery size ex vivo (indicators of arteriogenesis) and capillary contacts per fiber (CCF; an index of angiogenesis) in skeletal muscle of both sedentary and exercise-trained rats 14 days after bilateral occlusion of the femoral arteries. Total daily treadmill run time increased appreciably from approximately 70 to approximately 100 min (at 15-20 m/min, twice per day) and produced a large (approximately 75%, P < 0.01) increase in calf muscle blood flow and a greater size of the collateral artery (wall cross-sectional area). ZD4190, which previously has been shown to inhibit the activity of VEGF-R2 and -R1 tyrosine kinase in vitro (IC50 = 30 and 700 nM, respectively), completely blocked the increase in collateral-dependent blood flow and inhibited collateral vessel enlargement. Thus exercise-stimulated collateral arteriogenesis appears to be completely dependent on VEGF-R signaling. Interestingly, enhanced mRNA expression of the VEGF family ligand placental growth factor (2- to 3.5-fold), VEGF-R1 (approximately 2-fold), and endothelial nitric oxide synthase (2- to 3.5-fold) in an isolated collateral artery implicates these factors as important in arteriogenesis. Training of ischemic muscle also induced angiogenesis, as shown by an increase (approximately 25%, P < 0.01) in CCF in white gastrocnemius muscle. VEGF-R inhibition only partially blocked (P < 0.01) but did not eliminate the increase (P < 0.01) in capillarity. Our findings indicate that VEGF-R tyrosine kinase activity is essential for collateral arteriogenesis and important for the angiogenesis induced in ischemic muscle by exercise training; however, other angiogenic stimuli are also important for angiogenesis in flow-limited active muscle.
Pamela G Lloyd; Barry M Prior; Han Li; Hsiao T Yang; Ronald L Terjung
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-10-07
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  288     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-01-14     Completed Date:  2005-02-23     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H759-68     Citation Subset:  IM    
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri 65211, USA.
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MeSH Terms
Capillaries / physiology
Collateral Circulation / drug effects,  physiology
Gene Expression / drug effects,  physiology
Kidney / blood supply
Muscle, Skeletal / blood supply*,  physiology
Neovascularization, Physiologic / drug effects,  physiology*
Physical Conditioning, Animal
Physical Exertion / physiology*
Quinazolines / pharmacology*
Rats, Sprague-Dawley
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*,  genetics,  metabolism
Triazoles / pharmacology*
Grant Support
Reg. No./Substance:
0/Quinazolines; 0/Triazoles; 0/ZD 4190; EC, Vascular Endothelial Growth Factor

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