TY - JOUR
T1 - Nitric oxide-mediated vasodilation increases blood flow during the early stages of stress fracture healing
AU - Tomlinson, Ryan E.
AU - Shoghi, Kooresh I.
AU - Silva, Matthew J.
PY - 2014/2/15
Y1 - 2014/2/15
N2 - Despite the strong connection between angiogenesis and osteogenesis in skeletal repair conditions such as fracture and distraction osteogenesis, little is known about the vascular requirements for bone formation after repetitive mechanical loading. Here, established protocols of damaging (stress fracture) and nondamaging (physiological) forelimb loading in the adult rat were used to stimulate either woven or lamellar bone formation, respectively. Positron emission tomography was used to evaluate blood flow and fluoride kinetics at the site of bone formation. In the group that received damaging mechanical loading leading to woven bone formation (WBF), 15O water (blood) flow rate was significantly increased on day 0 and remained elevated 14 days after loading, whereas 18F fluoride uptake peaked 7 days after loading. In the group that received nondamaging mechanical loading leading to lamellar bone formation (LBF), 15O water and 18F fluoride flow rates in loaded limbs were not significantly different from nonloaded limbs at any time point. The early increase in blood flow rate after WBF loading was associated with local vasodilation. In addition, Nos2 expression in mast cells was increased in WBF-, but not LBF-, loaded limbs. The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester was used to suppress NO generation, resulting in significant decreases in early blood flow rate and bone formation after WBF loading. These results demonstrate that NO-mediated vasodilation is a key feature of the normal response to stress fracture and precedes woven bone formation. Therefore, patients with impaired vascular function may heal stress fractures more slowly than expected.
AB - Despite the strong connection between angiogenesis and osteogenesis in skeletal repair conditions such as fracture and distraction osteogenesis, little is known about the vascular requirements for bone formation after repetitive mechanical loading. Here, established protocols of damaging (stress fracture) and nondamaging (physiological) forelimb loading in the adult rat were used to stimulate either woven or lamellar bone formation, respectively. Positron emission tomography was used to evaluate blood flow and fluoride kinetics at the site of bone formation. In the group that received damaging mechanical loading leading to woven bone formation (WBF), 15O water (blood) flow rate was significantly increased on day 0 and remained elevated 14 days after loading, whereas 18F fluoride uptake peaked 7 days after loading. In the group that received nondamaging mechanical loading leading to lamellar bone formation (LBF), 15O water and 18F fluoride flow rates in loaded limbs were not significantly different from nonloaded limbs at any time point. The early increase in blood flow rate after WBF loading was associated with local vasodilation. In addition, Nos2 expression in mast cells was increased in WBF-, but not LBF-, loaded limbs. The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester was used to suppress NO generation, resulting in significant decreases in early blood flow rate and bone formation after WBF loading. These results demonstrate that NO-mediated vasodilation is a key feature of the normal response to stress fracture and precedes woven bone formation. Therefore, patients with impaired vascular function may heal stress fractures more slowly than expected.
KW - Bone formation
KW - L-NAME
KW - Stress fracture
KW - Vasodilation
KW - Woven
UR - http://www.scopus.com/inward/record.url?scp=84894270099&partnerID=8YFLogxK
U2 - 10.1152/japplphysiol.00957.2013
DO - 10.1152/japplphysiol.00957.2013
M3 - Article
C2 - 24356518
AN - SCOPUS:84894270099
SN - 8750-7587
VL - 116
SP - 416
EP - 424
JO - Journal of Applied Physiology
JF - Journal of Applied Physiology
IS - 4
ER -