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Herein, 4D-flow MRI was performed on the bilateral carotid arteries in a rat model of unilateral carotid artery injury to analyze changes in flow velocity, flow rate, wall shear stress (WSS), and cross-sectional area due to endothelial injury. MR images of the rat carotid artery were acquired using 7T-MRI. Seven control rats and 16 rats with right endothelial injury (VED) were used. For five of the VED models where blood flow in both the right and left common carotid arteries was confirmed, 4D-flow MRI was performed after obtaining 3D images using the time of flight method. MRI was performed to calculate the flow velocity, flow rate, WSS, and cross-sectional area of the proximal, middle, and distal carotid arteries. In all five VED models, blood flow rate and WSS were predominantly decreased at the proximal injured side compared to the ipsilateral control side ( p  < 0.05). The cross-sectional area of the vessel distal to the injured side of the VED model was reduced compared to that of the non-injured side ( p  < 0.05). A comparison of the proximal part of the uninjured side between the control group and VED model showed that the vascular cross-sectional area was predominantly increased in the VED model ( p  < 0.05). 4D-flow MRI with 7T-MRI enabled analysis of changes in flow velocity, flow rate, WSS, and cross-sectional area due to vascular endothelial injury.

Neointimal hyperplasia occurs in the context of vascular injury, such as stent intervention or balloon angioplasty. However, the role of mechanical forces in this process remains to be studied. In this study, a rat carotid artery intimal injury model was established. RNA-sequencing and transmission electron microscopy revealed that intimal injury disrupted the balance of vascular energy metabolism and impaired the mitochondrial ultrastructure in vivo. The human carotid plaque and femoral artery plaque samples also exhibited alterations in mitochondrial morphology. Vascular smooth muscle cells (VSMCs) are the main components of neointimal hyperplasia and are subjected to cyclic stretch resulting from pulsatile pressure. In this study, we found that the application of cyclic stretch in vitro increased VSMC mitochondrial mass and function. In addition, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) played an important role in regulating VSMC mitochondrial function in response to physiological stretch via the phosphorylation of Smad3. Increasing the activation of PGC1α by ZLN005 treatment effectively inhibited VSMC hyperproliferation after intimal injury in vivo. These results suggested that the regulation of PGC1α by p-Smad3 in response to physiological cyclic stretch may effectively alleviate neointimal hyperplasia by promoting mitochondrial function. PGC1α may be a potential therapeutic target for the prevention and treatment of neointimal hyperplasia.

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks (“middle-aged”) were compared to tissue or cells from mice aged 16 weeks (“adult”). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.

Background Atherosclerosis (AS) poses a pressing challenge in contemporary medicine. Glycolysis is a crucial bioenergetic metabolic pathway that provides the primary energy source for endothelial cells. Resveratrol (Res) is a natural compound that has been shown to possess AS. However, the underlying mechanisms of its anti-atherosclerotic effects are not yet fully understood. Methods We established a balloon injury model of the common carotid artery in Sprague-Dawley (SD) rats and an ox-LDL endothelial cell injury model for in vivo and in vitro experiments, respectively. Results Our study showed that 14 days after balloon-induced injury to the carotid intima of SD rats in vitro, the levels of glycolysis-related proteins fructose-2,6-bisphosphatase 3 (PFKFB3), glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) were increased. Meanwhile, Res treatment improved intimal hyperplasia and reduced the levels of expression of these glycolysis-related proteins, and with higher concentrations of Res leading to more pronounced improvements. In vivo, in ox-LDL HUVECs, Res reduced glucose uptake and lactate production, inhibited apoptosis, and decreased the expression of PFKFB3, GLUT1, HK2, and p-AKT. After the addition of a phosphatidylinositol 3-kinase (PI3K) inhibitor, the we established a balloon injury model of the common carotid artery in SD rats and an ox-LDL endothelial cell injury model for in vivo and in vitro experiments, respectively, and expression levels of p-AKT were observed to increase. Conclusion According to these findings, Resveratrol can reduce AS by influencing glycolysis and inhibiting apoptosis through the PI3K-AKT signalling pathway.

The novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive. The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo. In vitro, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay. In vivo, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury. Finerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling.

We have shown that both insulin and resveratrol (RSV) decrease neointimal hyperplasia in chow-fed rodents via mechanisms that are in part overlapping and involve the activation of endothelial nitric oxide synthase (eNOS). However, this vasculoprotective effect of insulin is abolished in high-fat-fed insulin-resistant rats. Since RSV, in addition to increasing insulin sensitivity, can activate eNOS via pathways that are independent of insulin signaling, such as the activation of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), we speculated that unlike insulin, the vasculoprotective effect of RSV would be retained in high-fat-fed rats. We found that high-fat feeding decreased insulin sensitivity and increased neointimal area and that RSV improved insulin sensitivity (p < 0.05) and decreased neointimal area in high-fat-fed rats (p < 0.05). We investigated the role of SIRT1 in the effect of RSV using two genetic mouse models. We found that RSV decreased neointimal area in high-fat-fed wild-type mice (p < 0.05), an effect that was retained in mice with catalytically inactive SIRT1 (p < 0.05) and in heterozygous SIRT1-null mice. In contrast, the effect of RSV was abolished in AMKPα2-null mice. Thus, RSV decreased neointimal hyperplasia after arterial injury in both high-fat-fed rats and mice, an effect likely not mediated by SIRT1 but by AMPKα2.

Despite advancements in drug-eluting stent technology, the incidence of in-stent restenosis (ISR) remains around 5–10%. The complex mechanisms of ISR are primarily based on the proliferation and migration of vascular smooth muscle cells (VSMCs). The dishevelled gene (DVL2), a component of the WNT signaling pathway, is involved in tumorigenesis. However, the role of DVL2 in ISR remains unknown. In this study, we used the rat carotid balloon injury model in vivo and PDGF-BB-treated VSMCs in vitro. Intimal hyperplasia was assessed by Hematoxylin and eosin staining. VSMCs proliferation was measured using EdU and CCK-8 assays, and migration was evaluated via transwell and Wound-healing assays. DVL2 expression was significantly increased in both balloon-injured carotid arteries and PDGF-BB-stimulated VSMCs. Knockdown of DVL2 using adeno-associated virus (AAV) effectively reduced intimal hyperplasia after balloon injury. Similarly, siRNA-mediated DVL2 silencing suppressed PDGF-BB-induced VSMCs proliferation and migration, whereas plasmid-driven DVL2 overexpression enhanced these effects. Additionally, DVL2 knockdown in PDGF-BB-stimulated VSMCs markedly upregulated the contractile markers α-smooth muscle actin and calponin. Mechanistically, DVL2 silencing inhibited β-catenin activation in PDGF-BB-treated VSMCs. Collectively, these findings demonstrated that DVL2 promoted VSMCs proliferation and migration by activating β-catenin signaling, highlighting its potential as a candidate therapeutic target for ISR.

Intimal hyperplasia (IH) remains a significant clinical problem, causing vascular intervention failure. This study aimed to elucidate whether gangliosides GA2 accumulated in atherosclerotic mouse aortae and plasma promote the development of IH. We identified that GA2 was remarkably accumulated in both artery and plasma of atherosclerotic patients and mice. Injected GA2 exacerbated IH and mainly co-stained with macrophages after mouse carotid arterial injury model. Intracellular GA2 induced pyroptosis accompanying the IL-1α release, which was blocked by caspase-11 knockout. Mechanistically, GA2 directly activated caspase-4 as a new ligand. And then, activated caspase-4/11 combined and cleaved BID, promoting the cytochrome C release to cytoplasm, which derived gasdermin E-medicated pyroptosis through activation of caspase-9-caspase-3 pathway. Mice transplanted with caspase-11 deficient bone marrow or mice with caspase-11 knockdown in macrophages exhibited an improvement of the IH aggravated by GA2. These findings suggest GA2-mediated caspase-4/11 activation drives macrophage pyroptosis, contributing to IH. Our results provide a potential diagnostic and therapeutic target in IH.

Background Endothelial progenitor cell (EPC) differentiation is considered crucial for vascular repair. Vascular endothelial growth factor (VEGF) induces EPC differentiation, but the underlying mechanism of this phenomenon remains unclear. Connexin 43 (Cx43) is reported to be involved in the regulation of stem cell differentiation. Therefore, we sought to determine whether Cx43 is involved in VEGF-induced EPC differentiation and vascular repair. Methods Rat spleen-derived EPCs were cultured and treated with various concentrations of VEGF (0, 10, or 50 ng/mL), and the relationship between EPC differentiation and Cx43 expression was evaluated. Thereafter, fluorescence redistribution after photobleaching was performed to assess the relationship between adjacent EPC differentiation and Cx43-induced gap junction intercellular communication (GJIC). After carotid artery injury, EPCs pretreated with VEGF were injected into the tail veins, and the effects of Cx43 on vascular repair were evaluated. Results EPCs cultured with VEGF exhibited accelerated differentiation and increased expression of Cx43. However, inhibition of Cx43 expression using short interfering RNA (siRNA) attenuated EPC GJIC and consequent EPC differentiation. VEGF-pretreated EPC transplantation promoted EPC homing and reendothelialization, and inhibited neointimal formation. These effects were attenuated by siRNA inhibition of Cx43. Conclusions Our results from in vivo and in vitro experiments indicated that VEGF promotes EPC differentiation and vascular repair through Cx43.

The study aims to explore the fluctuating expression of C/EBP Homologous Protein (CHOP) following rat carotid artery injury and its central role in vascular stenosis. Using in vivo rat carotid artery injury models and in vitro ischemia and hypoxia cell models employing human aortic endothelial cells (HAECs) and vascular smooth muscle cells (T/G HA-VSMCs), a comprehensive investigative framework was established. Histological analysis confirmed intimal hyperplasia in rat models. CHOP expression in vascular tissues was assessed using Western blot and immunohistochemical staining, and its presence in HAECs and T/G HA-VSMCs was determined through RT-PCR and Western blot. The study evaluated HAEC apoptosis, inflammatory cytokine secretion, cell proliferation, and T/G HA-VSMCs migration through Western blot, ELISA, CCK8, and Transwell migration assays. The rat carotid artery injury model revealed substantial fibrous plaque formation and vascular stenosis, resulting in an increased intimal area and plaque-to-lumen area ratio. Notably, CHOP is markedly elevated in vessels of the carotid artery injury model compared to normal vessels. Atorvastatin effectively mitigated vascular stenosis and suppresses CHOP protein expression. In HAECs, ischemia and hypoxia-induced CHOP upregulation, along with heightened TNFα, IL-6, caspase3, and caspase8 levels, while reducing cell proliferation. Atorvastatin demonstrated a dose-dependent suppression of CHOP expression in HAECs. Downregulation of CHOP or atorvastatin treatment led to reduced IL-6 and TNFα secretion, coupled with augmented cell proliferation. Similarly, ischemia and hypoxia conditions increased CHOP expression in T/G HA-VSMCs, which was concentration-dependently inhibited by atorvastatin. Furthermore, significantly increased MMP-9 and MMP-2 concentrations in the cell culture supernatant correlated with enhanced T/G HA-VSMCs migration. However, interventions targeting CHOP downregulation and atorvastatin usage curtailed MMP-9 and MMP-2 secretion and suppressed cell migration. In conclusion, CHOP plays a crucial role in endothelial injury, proliferation, and VSMCs migration during carotid artery injury, serving as a pivotal regulator in post-injury fibrous plaque formation and vascular remodeling. Statins emerge as protectors of endothelial cells, restraining VSMCs migration by modulating CHOP expression.