Inhibiting P-Pxn Promotes Bone Repair Through Neovessel Stabilization Promotion

Improving bone defect repair through vessel stabilization promotion A critical-size bone defect model was condstructed. Micro-CT, OCTA, EB extravasation assay, AFM were used to assess the vascular regeneration and critical-sized bone defect repair. We identified the p-Paxillin (p-PXN)-Rac signaling pathway, activated by extracellular matrix (ECM) stiffening, as a key mechanism driving vessel regression. By effectively inhibiting p-PXN, we achieved bone regeneration at an unprecedented pace. Specifically, we demonstrated that neovessel regression is closely linked to the progressive stiffening of the ECM caused by bone matrix mineralization and deposition. ECM stiffening disrupts the balance between neovessel formation and vascular maturation through p-PXN-Rac1-mediated mechanotransduction. This process increases angiogenic sprouting while decreasing pericyte recruitment and basement membrane (BM) component secretion, resulting in an immature and regression-prone vascular phenotype. Inhibiting p-PXN during the peak angiogenesis period (4 weeks post-bone injury) effectively delayed vessel regression, promoted vessel stabilization and boosted bone regeneration by 1.5-fold, achieving critical-sized bone defect healing at an unprecedented rate. Extracellular matrix stiffening promoted sprouting angiogenesis while decreased pericytes recruitment and basement membrane secretion, thus resulted in an imbalance between neovessels formation and vascular maturation by p-PXN-Rac1-mediated mechanotransduction, eventually leading to the prone-to-regressed vascular phenotype. Retarded vessel regression and enhanced critical-sized bone defect healing were successfully achieved through p-PXN inhibition at 4 weeks post-surgery.