Mechanical loading-induced bone formation is associated with increased blood velocity and vascular canal bone...

Bone is a highly vascularized tissue, which is required for the metabolically demanding process of remodeling. Blood vessels are important in fluid movement occurring during bone mechanoadaptation. We hypothesized that in-vivo mouse tibial loading, which does not involve muscle contraction and exercise-associated cardiovascular effects, would lead to acute and chronic changes in femoral, saphenous, and popliteal artery structure and function, as well as bone vascular porosity coincident with adaptive bone (re)modeling. Sixteen, 26-wk-old female C57BL/6 J mice received two weeks of once, daily in vivo cyclic loading to the left tibia, resulting in increased cortical bone formation with minimal changes to trabecular bone. In vivo microCT-based timelapse morphometry revealed that most formation occurred on the endocortical surface. Ultrasonography showed changes to blood velocity after each loading episode (days 1, 3, 7, and 9) in saphenous and popliteal arteries, with the femoral artery adapting later. Chronic changes to blood velocity (Δ from baseline) were seen only in the femoral and popliteal vessels closely associated with the loaded tibia. Microfil contrast agent perfused into the vasculature showed minimal loading-induced changes in overall limb vascularity and confirmed targeted popliteal adaptation. Synchrotron tomography revealed greater cortical bone vascular canal porosity in the metaphysis, but not mid-diaphysis of loaded versus non-loaded tibiae. We measured an increased osteocyte lacunar number density surrounding blood vessels in loaded limbs, with no increase found in the canalicular density. Overall, loading led to both temporal and spatially dependent adaptation in the vasculature in the hindlimb and the bone tissue at the level of the primary limb arteries, intracortical bone blood vessels, as well as the osteocyte lacunocanalicular network architecture surrounding the blood vessels. These results highlight the critical role of local vascular dynamics in orchestrating bone adaptation, with implications for developing precision therapies that modulate the vasculature to enhance skeletal resilience.