title: Nitric oxide-mediated vasodilation increases blood flow during the early stages of stress fracture healing.
abstract: 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), (15)O water (blood) flow rate was significantly increased on day 0 and remained elevated 14 days after loading, whereas (18)F fluoride uptake peaked 7 days after loading. In the group that received nondamaging mechanical loading leading to lamellar bone formation (LBF), (15)O water and (18)F 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 N(ω)-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.
authors.affiliation: Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, Missouri;
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Tomlinson
authors.forename: Kooresh I
authors.initials: KI
authors.lastname: Shoghi
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Silva
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017102:Fracture Healing / Q000187:drug effects; D015775:Fractures, Stress / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D049268:Positron-Emission Tomography; D051381:Rats; D011916:Rats, Inbred F344; D012039:Regional Blood Flow; D013997:Time Factors; D014457:Ulna / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014458:Ulna Fractures / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D016474:Weight-Bearing
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: bone formation; l-NAME; stress fracture; vasodilation; woven