Mechanical loading-induced bone formation is associated with increased blood velocity and vascular canal bone porosity, with localized vascular adaptation

Bone is a highly vascularized tissue, which is useful for the metabolically demanding process of remodeling. Blood vessels are important in the fluid movement that occurs 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 immediate and long-term changes in femoral, saphenous, and popliteal artery structure, as well as bone vascular porosity coincident with adaptive bone (re)modeling. Sixteen, 26-wk-old female C57BL/6J mice received 2 wks 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 micro-CT-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 the 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 in the mid-diaphysis of loaded vs non-loaded tibiae. We measured an increased osteocyte lacunar number density surrounding blood vessels in loaded limbs, but 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 plasticity and important contribution to orchestrating bone adaptation, with implications for developing precision therapies that modulate the vasculature to enhance skeletal resilience.