Rotator cuff healing is regulated by the lymphatic vasculature.

Background: Despite great advances in surgical techniques for rotator cuff tear (RCT) over the past decades, the postoperative failure rate of RCT is still high due to the poor healing competence of bone-tendon interface (BTI). The lymphatic vasculature plays a regulatory role in inflammatory disease and affects tissue healing. However, whether lymphangiogenesis and the role of lymphatic vasculature in the physiopathological process of rotator cuff （RC）injury remains unknown. Methods: In this study, we constructed a mouse RC injury model and the BTI samples were collected for measurement. Firstly, immunofluorescence was used to investigate the temporal and spatial distribution of lymphangiogenesis in BTI area at different post-injury time points. Subsequently, the mice of experimental group were gavaged with the lymphatic inhibitors (SAR131675) on the first postoperative day to inhibit lymphangiogenesis, while the control group was treated with the vehicle. At postoperative week 2 and 4, the samples were collected for immunofluorescence staining to evaluate lymphatic angiogenesis inhibition. At postoperative week 4 and 8, The supraspinatus (SS) tendon-humeral complexes were collected for bone morphometric, histological and biomechanical tests to assess the healing outcome of the BTI. Results: Immunofluorescence results showed that the lymphatic proliferation in the BTI injury area and increased in consistence with the healing time, and the lymphatic hyperplasia area significantly diminished at postoperative week 4. The lymphatic hyperplasia area in the SAR group was significantly lower than that in the control group both at 2 and 4 weeks postoperatively. Moreover, the administration of SAR131675 significantly impeded RC healing, as evidenced by lower histological scores, lower bone morphometric parameters, and worse biomechanical properties in comparison with that in control group at postoperative weeks 4 and 8. Conclusion: Lymphangiogenesis plays a positive role in RC healing, and targeting the lymphatic drainage at healing site may be a new therapeutic approach to promote RC injury repair. The translational potential of this article: This is the first study to assess the specific role of lymphatic vessels in RC healing, and improving lymphatic drainage may be a potential new therapeutic approach to facilitate repair of BTI. Further, our study provides a reference for possible future treatment of BTI by intervening the lymphatic system.