PIEZO1-activated donor lymphatic remodeling integrates with autologous lymphangiogenesis to enhance vein graft patency in mice.

Abstract

The great saphenous vein is the most commonly used conduit in coronary artery bypass grafting; however, the high vein graft failure rates remain an unresolved issue. Here, we compared different harvesting techniques for mouse vein grafts and found that the construction of a denser lymphatic network contributed to improved vein graft patency. Dual lymphatic tracing strategies using <i>Lyve1</i>-Cre^ER;R26-tdTomato/zsGreen mice uncovered a heterogeneous lymphatic network in mouse vein grafts. The anastomotic delivery of a lymphangiogenic signal, vascular endothelial growth factor-C_156S, upon surgical completion promoted autologous lymphangiogenesis. The preservation of surrounding tissue led to donor-derived lymphatic remodeling dependent on PIEZO1-induced CD44 cleavage. The autologous and donor-derived lymphatic structures integrated with each other in the anastomotic area, and the loss of either component aggravated inflammation-associated neointima formation. Obesity was identified as an independent factor in mouse- and patient-derived venous samples, contributing to the perivenous macrophage accumulation and functional lymphatic remodeling, which intensified the vein graft benefits induced by surrounding tissue preservation. Collectively, this study provides both preoperative and perioperative therapeutic strategies to improve vein grafts and shows that preserving perivenous lymphatic vessels or promoting autologous lymphangiogenesis could enhance vein graft patency.