FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds.

Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage-specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to reduced endothelial cell proliferation, reduced angiogenesis, and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression. In a porcine dermal wound-healing model that closely resembles healing in humans, local application of a FOXO1 inhibitor reduced angiogenesis. This is the first report that FOXO1 directly regulates VEGFA expression and that FOXO1 is needed for normal angiogenesis during wound healing. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Effect of scapular dyskinesis on supraspinatus repair healing in a rat model.

BACKGROUND: Rotator cuff tears are common conditions that often require surgical repair to improve function and to relieve pain. Unfortunately, repair failure remains a common problem after rotator cuff repair surgery. Several factors may contribute to repair failure, including age, tear size, and time from injury. However, the mechanical mechanisms resulting in repair failure are not well understood, making clinical management difficult. Specifically, altered scapular motion (termed scapular dyskinesis) may be one important and modifiable factor contributing to the risk of repair failure. Therefore, the objective of this study was to determine the effect of scapular dyskinesis on supraspinatus tendon healing after repair. METHODS: A rat model of scapular dyskinesis was used. Seventy adult male Sprague-Dawley rats (400-450 g) were randomized into 2 groups: nerve transection of the accessory and long thoracic nerves (SD) or sham nerve transection (Sham control). After this procedure, all rats underwent unilateral detachment and repair of the supraspinatus tendon. All rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function, passive joint mechanics, and tendon properties (mechanical, histologic, organizational, and compositional) were evaluated. RESULTS: Scapular dyskinesis alters joint function and may lead to compromised supraspinatus tendon properties. Specifically, diminished mechanical properties, altered histology, and decreased tendon organization were observed for some parameters. CONCLUSION: This study identifies scapular dyskinesis as one underlying mechanism leading to compromise of supraspinatus healing after repair. Identifying modifiable factors that lead to compromised tendon healing will help improve clinical outcomes after repair.

Overuse activity in the presence of scapular dyskinesis leads to shoulder tendon damage in a rat model.

Shoulder tendon injuries are common clinical conditions and are a significant source of pain and dysfunction. These conditions are more common in individuals who perform repetitive overhead activities and in individuals who have abnormal scapular kinematics, termed scapular dyskinesis (SD). However, the long term consequences associated with overuse activity in the presence of SD are unknown. Therefore, the objective of this study was to determine the effect of overuse in combination with SD on joint mechanics and properties of the rotator cuff and biceps tendons. A rat model of scapular dyskinesis was used. Ninety adult male Sprague-Dawley rats (400-450 g) were randomized into three groups: nerve transection (SD), sham nerve transection + overuse (OV), or nerve transection + overuse (SD + OV). Rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function and passive joint mechanics were evaluated over time and tendon properties (mechanical, histological, organizational, and compositional) were measured. Results demonstrated that overuse activity and SD are each independently detrimental to tendon properties (e.g., diminished mechanical properties, disorganized collagen). However, tendon damage caused by the addition of overuse may be worse, with more parameters altered, than damage caused by the addition of SD. This study helps define the mechanical mechanisms leading to tendon damage and provides a framework for distinguishing treatment strategies for active patients and those with abnormal scapular mechanics.

Scapular dyskinesis is detrimental to shoulder tendon properties and joint mechanics in a rat model.

Shoulder tendon injuries are frequently seen in the presence of abnormal scapular motion, termed scapular dyskinesis. The cause and effect relationship between scapular dyskinesis and shoulder injury has not been directly defined. We developed and used an animal model to examine the initiation and progression of pathological changes in the rotator cuff and biceps tendon. Sixty male Sprague-Dawley rats were randomized into two groups: nerve transection (to induce scapular dyskinesis, SD) or sham nerve transection (control). The animals were euthanized 4 and 8 weeks after surgery. Shoulder function and passive joint mechanics were evaluated over time. Tendon mechanical, histological, organizational, and compositional properties were evaluated at both time points. Gross observation demonstrated alterations in scapular motion, consistent with scapular "winging." Shoulder function, passive internal range of motion, and tendon mechanical properties were significantly altered. Histology results, consistent with tendon pathology (rounded cell shape and increased cell density), were observed, and protein expression of collagen III and decorin was altered. This study presents a new model of scapular dyskinesis that can rigorously evaluate cause and effect relationships in a controlled manner. Our results identify scapular dyskinesis as a causative mechanical mechanism for shoulder tendon pathology.