Increase of both angiogenesis and bone mass in response to exercise depends on VEGF.
Physiological angiogenesis during bone remodeling is undefined. Treadmill-running rats displayed bone marrow angiogenesis concomitant with bone formation increase and resorption decrease and upregulation of VEGF and its R1 receptor mRNA in proximal tibia. VEGF blockade over 5 weeks of training fully prevented the exercise-induced bone mass gain.


BACKGROUND
We investigated the role of vascular endothelial growth factor (VEGF) and angiogenesis in the osteogenic response to exercise.


METHODS
Nine-week-old male Wistar rats were treadmill-trained at 60% Vo(2max) for various periods. Bone and vascular histomorphometry was performed after 2- and 5-week experiments. On-line RT PCR for VEGF and its receptors R1 and R2 was done after a 10-day experiment. In the 5-week experiment, running rats received either a VEGF inhibitory antibody or a placebo.


RESULTS
After 2 weeks, tibial BMD did not change; however, vessel number in the proximal metaphysis increased by 20% in running versus sedentary rats. In running rats, vessel number correlated positively (r = 0.88) with bone formation rate and negatively (r = -0.85) with active resorption surfaces. After 10 days of training, upregulation of VEGF and VEGF receptor R1 mRNA was detected in periosteum and metaphyseal bone. VEGF blockade in 5-week trained rats fully prevented the exercise-induced increase in metaphyseal BMD (9%) and cancellous bone volume (BV/TV; 25%), as well as the increased vessel number (25%). In 5-week placebo-treated running rats, bone formation rate returned to initial values, whereas osteoclastic surfaces continued to decline compared with both sedentary and anti-VEGF-treated running rats.


CONCLUSIONS
VEGF signaling-mediated bone angiogenesis is tightly related to exercise-induced bone cellular uncoupling and is indispensable for bone gain induced by exercise.
Yao
Zhenqiang
Z
Faculté de Médecine, Laboratoire de Biologie du Tissu Osseux, Saint-Etienne Cedex 02 42023, France.
Lafage-Proust
Marie-Hélène
MH
Plouët
Jean
J
Bloomfield
Susan
S
Alexandre
Christian
C
Vico
Laurence
L
D000818:Animals; D015519:Bone Density; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D008297:Male; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009929:Organ Size; D010012:Osteogenesis / Q000502:physiology*; D010521:Periosteum / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D013977:Tibia / Q000098:blood supply* / Q000166:cytology / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor