Role of FOXM1 in vascular smooth muscle cell survival and neointima formation following vascular injury

Abstract

Background: Accelerated smooth muscle cell (SMC) proliferation is the primary cause of intimal hyperplasia (IH) following vascular interventions. Forkhead Box M1 (FOXM1) is considered a proliferation-associated transcription factor. However, the presence and role of FOXM1 in IH following vascular injury have not been determined. Objective: We examined the expression of FOXM1 in balloon-injured rat carotid arteries and investigated the effect of FOXM1 inhibition in SMCs and on the development of IH. Methods and results: FOXM1 was detected by immunofluorescent staining in balloon-injured rat carotid arteries where we observed an upregulation at day 7, 14, and 28 compared to uninjured controls. Immunofluorescence staining revealed FOXM1 coincided with proliferating cell nuclear antigen (PCNA). FOXM1 was also detectable in human carotid plaque samples. Western blot showed an upregulation of FOXM1 protein in serum-stimulated SMCs. Inhibition of FOXM1 using siRNA or chemical inhibition led to the induction of apoptosis as measured by flow cytometry and western blot for cleaved caspase 3. Perturbations in survival signaling were measured by western blot following FOXM1 inhibition, which showed a decrease in phosphorylated AKT and β-catenin. The chemical inhibitor thiostrepton was delivered by intraperitoneal injection in rats that underwent balloon injury and led to reduced intimal thickening compared to DMSO controls. Conclusions: FOXM1 is an important molecular mediator of IH that contributes to the proliferation and survival of SMCs following vascular injury.

MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription

“…Our data indicate that MKL1 regulates VSMC proliferation via redox-sensitive FOXM1 trans -activation reaffirming a previous finding by Park et al that oncogenic induction of FOXM1 in mouse embryonic fibroblasts (MEFs) is ROS-dependent [ 44 ]. This is also consistent with a previous report by Franco et al in which increased FOXM1 expression was detected in the carotid arteries of rats subjected to balloon injury [ 50 ]. Additional corroborating evidence can also be drawn from a study wherein Dai et al harnessed both VSMC-specific gain-of-function and loss-of-function FOXM1 transgenic mouse models to demonstrate a positive correlation between FOXM1 and VSMC proliferation in the context of pulmonary hypertension [ 51 ].…”

“…In summary, our data unveil a previously unrecognized MK2-MKL1-FOXM1 axis that functions as a redox-sensitive switch to regulate VSMC proliferation and neointima formation. In light of the findings that both MK2 inhibitor [ 58 ] and FOXM1 inhibitor [ 50 ] show high efficacy in blocking neointima formation in model animals, our data provide renewed rationale that targeting this MK2-MKL1-FOXM1 axis is a feasible therapeutic approach in preventing restenosis.…”

Injectable Hydrogel Capable of In Situ Covalent Crosslinking for Permanent Embolization

“…Collectively, the DCN hydrogel group showed acute occlusion of the treated artery and induced a continuous increase in collagen with cellular proliferation, which are histological characteristics of the luminal occlusion/narrowing by the intimal hyperplasia of the artery. − In the clinical setting, recanalization of the treated artery and aneurysm is a major concern, , especially after the endovascular treatment of the large artery, like an aortic aneurysm . The DCN hydrogel group showed both acute thrombosis of the targeted artery and delayed fibrotic changes with continued occlusion by the cellular component.…”

Stimulus-Responsive Zwitterionic Prodrug Delivery System with Sustained Release of Hydrogen Sulfide for Protective Aortic Dissection

“…H 2 S plays an important role in SMC pathology in pulmonary hypertension, according to recent studies. Vascular remodeling was observed where SMC proliferation was noted . The unregulated breakdown of elastic media that involves SMC pathology is one of the main causes of clinical vasculopathy .…”

“…Vascular remodeling was observed where SMC proliferation was noted. 10 The unregulated breakdown of elastic media that involves SMC pathology is one of the main causes of clinical vasculopathy. 11 Meanwhile, SMCs are plastic and alter their morphology and proliferate and migrate, hence performing contractile and synthetic functions.…”