Prolymphangiogenic Effects of 9- Retinoic Acid Are Enhanced at Sites of Lymphatic Injury and Dependent on Treatment Duration in Experimental Postsurgical Lymphedema.

Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9- retinoic acid (9- RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Short-duration treatment with 9- RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9- RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Given the reported results indicating that 9- RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9- RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema.