LIM and Cysteine-Rich Domains 1 Mediated Flow-Dependent Vein Graft Remodeling

Abstract

Background: Neointimal hyperplasia (NIH)-induced vein graft remodeling poses a challenge for coronary artery bypass grafting surgery. Despite the crucial influence of hemodynamic conditions on vein graft remodeling, the specific mediators orchestrating cellular processes and morphological changes during this process remain unclear. A comprehensive understanding of flow-mediated NIH is essential for developing preventive strategies. Methods: Sprague-Dawley (SD) rats were utilized to establish a vein transplantation model, manipulating flow states by ligating the distal carotid branch. Graft tissues exposed to high-flow and low-flow conditions were assessed at control, Day 7, Day 14, and Day 28 time points to evaluate the neointimal area and cell phenotypes using histological staining. Immunofluorescence staining was employed to examine LIM and cysteine-rich domains 1 (Lmcd1) gene expression under different flow conditions. Additionally, changes in NIH were observed in SD rats through adeno-associated viral gene transfer of Lmcd1 short hairpin RNA (shRNA). Results: The model demonstrated an immediate decrease in mean flow rates of vein grafts over the 28-day period following ligation of the carotid artery branch (p < 0.0001). This significantly increased the intimal area, which progressively rose until day 28 (p < 0.05). Low-flow arterial hemodynamic conditions markedly downregulated the expression of characteristic mature muscle markers and significantly upregulated cell proliferation, Lmcd1, and phosphoinositide 3-kinase (PI3K) pathway. Gene transfer of Lmcd1 shRNA inhibited PI3K pathway activation, promoted the adoption of a mature phenotype by neointimal cells, and reduced neointimal area in low-flow vein grafts compared to controls (p < 0.01). Conclusions: Distinct vein graft remodeling patterns arise from flow environment alterations. The observed increase in NIH in low-flow grafts is associated with differentially expressed Lmcd1, which regulates the PI3K pathway, influencing the phenotypic modulation of cells within the neointima. Perturbations in Lmcd1 activity regulate the PI3K pathway and contribute to maladaptive vascular remodeling under reduced blood flow conditions.