Four and a half Lin11, Isl-1, Mec-3(LIM) domain protein 1 (FHL1) regulates vascular remodeling in low-flow vein...

Neointimal hyperplasia (NIH) is a critical determinant of long-term patency of vein grafts following coronary artery bypass grafting (CABG). The development of neointima is influenced by hemodynamic conditions. Our previous studies have demonstrated that four and a half LIM domain protein 1 (FHL1) effectively attenuates neointimal formation in vein grafts under normal flow conditions. However, the role of FHL1 in low-flow hemodynamic environments remains unclear. Elucidating the mechanisms underlying NIH in low-flow settings is essential for improving low-flow vein graft outcomes.

The vein graft model was established in Sprague-Dawley (SD) rats, with low blood flow induced by ligation of the internal carotid artery. Then eointimal area was quantified using histological staining, while the expression of neointimal markers was assessed via immunofluorescence analysis. FHL1-knockout SD rats and SD rats with adenovirus-mediated FHL1 overexpression were used to evaluate the progression of NIH under low-flow conditions.

Following internal carotid artery ligation, the mean blood flow velocity in the vein grafts decreased immediately (p < 0.0001), resulting in a significant increase in the neointimal area at 28 days post-surgery (p < 0.05). In FHL1-knockout rats under low-flow conditions, NIH was further exacerbated (p < 0.001), accompanied by marked downregulation of mature smooth muscle cell markers (p < 0.05) and decreased proliferative activity (p < 0.0001), reduced inflammatory mediators (p < 0.0001), and activation of the mitogen-activated protein kinase (MAPK) signaling pathway (p < 0.01). Conversely, FHL1 overexpression in low-flow grafts led to a reduction in neointimal thickening (p < 0.05), promoted phenotypic maturation of neointimal cells (p < 0.05), and suppressed proliferative activity (p < 0.05), MAPK pathway activation (p < 0.01), and inflammatory responses (p < 0.01).

In low-flow vein grafts, FHL1 may promote favorable vascular remodeling by inhibiting the MAPK signaling pathway, thereby attenuating neointimal cell phenotype switching and mitigating vascular inflammation.