Temporal vascular pattern remodeling mediated by the FHL2/sFRP2 signaling pathway in tenocytes affects tendon repair and regeneration

Although angiogenesis following tendon injury was expected to provide nutrients for regeneration and repair, excessive angiogenesis may be associated with poor long-term outcomes in tendinopathy. Here we aim to explore the pathological role of angiogenesis in the progression of tendinopathy. Patients with tendinopathy were categorized into a hypervascularization group (HyperV) and a hypovascularization group (HypoV), and postarthroscopic outcome and histopathology were compared. In addiiton, tendon injury models and tenocyte stress models were employed to investigate the temporal-spatial vascular pattern characteristics and mechanisms involved in the progression of tendinopathy. This study finds that the HyperV group exhibited worse postoperative pain and functional outcomes and higher Bonar's pathological scores and vascular density. Bulk RNA sequencing and pathological staining revealed that decreased FHL2 and increased YAP1/sFRP2 expression in tenocytes were strongly associated with disorganized tissue pathology, aggravated inflammation and increased vascular abundance in the HyperV group and tendon injury models (Td-Inj and Td-Sut groups). Three-dimensional vascular imaging demonstrated the formation of morphologically complex and abnormally distributed blood vessels in the Td-Inj and Td-Sut groups, which was significantly alleviated by YAP1 knockdown. In activated tenocytes, FHL2 deficiency-mediated YAP1 overexpression led to the overexpression and extracellular secretion of sFRP2, thereby enhancing endothelial angiogenesis. FHL2 overexpression partly mitigated vascular remodeling and improved tendon blood perfusion in rats. In summary, FHL2/YAP1/sFRP2-mediated pathological vascular remodeling disrupts the homeostasis of tendon repair and regeneration. This study underscores the importance of a systematic vascular assessment, incorporating abundance, morphology, and spatial distribution, in tendinopathy.