Restoration Of Blood Flow Research Articles

Involvement of Inflammation in Venous Thromboembolic Disease

Recent evidence has been established that the inflammatory process is involved in the pathophysiology of Venous Thrombotic Events (VTE) and may have a significant role in prediction of the disease. It is likely that classical and non-classical risk factors modulate thrombosis through inflammatory mediators. Inflammation of the venous wall promotes the release of tissue factor inhibit the release of anticoagulant factors and hamper endogenous fibrinolysis. Recent studies also indicated that increased inflammatory response (interleukin storm) is related to prothrombotic state and thromboembolic events in patients with COVID-19. Inflammatory markers are also negatively related to thrombolysis and restoration of blood flow in the acute phase of Venous Thrombosis (VT). Despite the growing evidence of the involvement of inflammation in pathogenesis of VTE, the importance of anti-inflammatory treatment of this disease was overlooked. Aspirin was shown to be effective in the prevention of recurrent venous thrombosis after treatment with anticoagulant drugs. Some anti-inflammatory drugs like nonsteroidal anti-inflammatory agents may have prothrombotic effect and increase risk of VTE. Therefore, the recent research was dedicated to searching new specific anti-inflammatory drug inhibitors of inflammatory markers, which were shown to be involved in the pathogenesis of VTE. As thrombus formation is based on the activation of coagulation system, provoked by inflammation, prevention and treatment of VTE, should include both anticoagulant and anti-inflammatory agents. To reduce bleeding complications of combined treatment, sub-therapeutic doses of both drugs should be used to improve the efficacy of management of VTE without increasing risk of bleeding.

Endovascular therapy in acute mesenteric ischemia after coronary artery bypass grafting: a case report and literature review

In the pattern of abdominal complications after cardiac surgery, acute mesenteric ischemia is rare but high-mortality pathology. In the initial stages, the disease has no specific signs, which makes it difficult to perform early multislice computed tomography to diagnose it. Risk stratification and an individual approach to the choice of diagnostic and therapeutic measures aimed at early restoration of mesenteric blood flow will reduce the mortality in this complication.

Exogenous Hydrogen Sulfide Plays an Important Role Through Regulating Autophagy in Ischemia/Reperfusion Injury.

Ischemia/reperfusion (I/R) injury is characterized by limiting blood supply to organs, then restoring blood flow and reoxygenation. It leads to many diseases, including acute kidney injury, myocardial infarction, circulatory arrest, ischemic stroke, trauma, and sickle cell disease. Autophagy is an important and conserved cellular pathway, in which cells transfer the cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. Hydrogen sulfide (H2S), along with carbon monoxide (CO) and nitric oxide (NO), is an important gas signal molecule and regulates various physiological and pathological processes. In recent years, there are many studies on the improvement of I/R injury by H2S through regulating autophagy, but the related mechanisms are not completely clear. Therefore, we summarize the related research in the above aspects to provide theoretical reference for future in-depth research.

Galectin-1 Contributes to Vascular Remodeling and Blood Flow Recovery After Cerebral Ischemia in Mice.

Galectin-1 is found in the vasculature and has been confirmed to promote angiogenesis in several cancer models. Furthermore, galectin-1 has been demonstrated to improve the recovery of cerebral ischemia. However, whether vascular remodeling contributes to this improvement is still unknown. In the present study, photochemical cerebral ischemia was induced in both galectin-1-treated (2μg/day, i.c.v, 3days) and galectin-1 knockout mice. Laser speckle imaging and immunofluorescent staining demonstrated that circulation and vascular remodeling in the ischemic cortex were improved by galectin-1 treatment but disrupted in galectin-1 knockout mice. Western blot analysis showed that the expression of matrix metallopeptidase-9 and vascular endothelial growth factor (VEGF) was regulated by galectin-1 in vivo. To determine how galectin-1 influences endothelial cells, the expression of galectin-1 in bEnd.3 cells was increased by transfection with an expression plasmid and knocked down by siRNA. As demonstrated by quantitative RT-PCR and western blot analysis, the expression of metallopeptidase-9, VEGF, and VEGF receptors was upregulated by galectin-1 overexpression but downregulated after galectin-1 knockdown. Flow cytometry, Transwell assay, and capillary-like tube formation assay were performed on cells after gene manipulation as well as cells treated by exogenous galectin-1 after anoxia. It demonstrated that galectin-1 potentiated the cell proliferation, migration capacity, and tube formation ability. Taken together, these data suggest that by targeting vascular remodeling, galectin-1 contributes to the restoration of blood flow, which promotes the recovery of mice after cerebral ischemic insults.

Enhanced expression of P2X4 purinoceptors in pyramidal neurons of the rat hippocampal CA1 region may be involved ischemia-reperfusion injury.

Ischemic stroke is the most serious disease that harms human beings. In principle, its treatment is to restore blood flow supply as soon as possible. However, after the blood flow is restored, it will lead to secondary brain injury, that is, ischemia-reperfusion injury. The mechanism of ischemia-reperfusion injury is very complicated. This study showed that P2X4 receptors in the pyramidal neurons of rat hippocampus were significantly upregulated in the early stage of ischemia-reperfusion injury. Neurons with high expression of P2X4 receptors are neurons that are undergoing apoptosis. Intraventricular injection of the P2X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) and PSB-12062 can partially block neuronal apoptosis, to promote the survival of neurons, indicating that ATP through P2X4 receptors is involved in the process of cerebral ischemia-reperfusion injury. Therefore, identifying the mechanism of neuronal degeneration induced by extracellular ATP via P2X4 receptors after ischemia-reperfusion will likely find new targets for the treatment of ischemia-reperfusion injury, and will provide a useful theoretical basis for the treatment of ischemia-reperfusion injury.

Suprachoroidal haemorrhage (SCH) drainage using suprachoroidal tissue plasminogen activator (t-PA) after complicated cataract extraction (two-staged procedure): early intervention could mean better vision

Tissue plasminogen activator (t-PA) is a thrombolytic agent that converts plasminogen to active plasmin. Rapid thombolysis can restore blood flow or assist drainage. Therapeutic recombinant t-PA (rt-PA), first trialled in...

Reversal of Aging‐Associated Vasoreparative Dysfunction and Myelopoietic Bias in Bone Marrow Stem/Progenitor Cells by Angiotensin‐(1‐7)

Aging increases risk for ischemic vascular diseases. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) are known to stimulate vascular regeneration. However, aging impairs vasoreparative functions and myelopoietic bias in HSPCs. The alternative axis of renin-angiotensin system, angiotensin converting enzyme-2 (ACE2)/ angiotensin-(1-7) (Ang-(1-7)/Mas receptor (MasR), is vasoprotective in contrast to the canonical pathway ACE/Ang II/AT1 receptor. This study tested if MasR activation by Ang-(1-7) restores vasoreparative functions in HSPCs derived from aging mice. Lin-Sca-1+cKit+ (LSK) cells were isolated from Young (3-5 months) (n=10) or Old (20-22 months) (n=10) mice, and migration and proliferation were evaluated. Old mice were treated with Ang-(1-7) (1 µg/Kg/min, four weeks). Hindlimb ischemia was induced by femoral ligation, and mobilization of LSK cells into the blood circulation was determined. Blood flow recovery was monitored by Laser Doppler blood flow meter and vascular density was evaluated by immunohistochemistry for CD31 and isolectin B4-positive structures. Myeloid cells in bone marrow were evaluated by colony forming unit (CFU) assay for granulocyte-macrophage differentiation, followed by flow cytometry of monocyte (Ly6G-CD11b+Ly6Chi) and macrophage (Ly6G-CD11b+F4/80+Ly6Chi) populations. Pro-myelopoietic factors, S100A8/A9, in the bone marrow supernatant were probed by western blotting. Old mice have decreased number of LSK cells in the circulation with reduced migration or proliferation in response to stromal-derived factor-1α, compared to Young (n=6). These dysfunctions were reversed by Ang-(1-7). Ischemia increased the number of circulating LSK cells in Young mice and restored blood flow to ischemic areas (n=6). These responses were impaired in Old mice but were restored by treatment with Ang-(1-7) (n=6). Neovascularization of ischemic areas is reduced in old mice compared to the Young and was restored by Ang-(1-7) (n=4). CFU assay revealed that myelopoiesis is upregulated in the Old bone marrow (increased differentiation into monocyte-macrophage populations) with increased levels of S100A8/A9, compared to the Young. Treatment of Old mice with Ang-(1-7), decreased myelopoietic differentiation and S100A8/A9 concentration to similar levels as in Young (n=4). These results suggest that activation of MasR would be a promising approach for enhancing vasoreparative potential of stem/progenitor cells in aging.

The Protective Mechanism of Dexmedetomidine in Regulating Atg14L-Beclin1-Vps34 Complex Against Myocardial Ischemia-Reperfusion Injury.

The blood flow restoration of ischemic tissues causes myocardial injury. Dexmedetomidine (Dex) protects multi-organs against ischemia/reperfusion (I/R) injury. This study investigated the protective mechanism of Dex post-treatment in myocardial I/R injury. The rat model of myocardial I/R was established. The effects of Dex post-treatment on cardiac function and autophagy flow were observed. Dex attenuated myocardial I/R injury and reduced I/R-induced autophagy in rats. Dex weakened the interactions between Beclin1 and Vps34 and Beclin1 and Atg14L, thus downregulating Vps34 kinase activity. In vitro, the cardiomyocytes subjected to oxygen glucose deprivation/reoxygenation were treated with Dex and PI3K inhibitor LY294002. LY294002 attenuated the myocardial protective effect of DEX, indicating that Dex protected against cardiac I/R by activating the PI3K/Akt pathway. In conclusion, Dex upregulated the phosphorylation of Beclin1 at S295 site by activating the PI3K/Akt pathway and reduced the interactions of Atg14L-Beclin1-Vps34 complex, thus inhibiting autophagy and protecting against myocardial I/R injury.

Post-ischemic Myocardial Inflammatory Response: A Complex and Dynamic Process Susceptible to Immunomodulatory Therapies.

Following acute occlusion of a coronary artery causing myocardial ischemia and implementing first-line treatment involving rapid reperfusion, a dynamic and balanced inflammatory response is initiated to repair and remove damaged cells. Paradoxically, restoration of myocardial blood flow exacerbates cell damage as a result of myocardial ischemia–reperfusion (MI-R) injury, which eventually provokes accelerated apoptosis. In the end, the infarct size still corresponds to the subsequent risk of developing heart failure. Therefore, true understanding of the mechanisms regarding MI-R injury, and its contribution to cell damage and cell death, are of the utmost importance in the search for successful therapeutic interventions to finally prevent the onset of heart failure. This review focuses on the role of innate immunity, chemokines, cytokines, and inflammatory cells in all three overlapping phases following experimental, mainly murine, MI-R injury known as the inflammatory, reparative, and maturation phase. It provides a complete state-of-the-art overview including most current research of all post-ischemic processes and phases and additionally summarizes the use of immunomodulatory therapies translated into clinical practice.

PPARγ in Ischemia-Reperfusion Injury: Overview of the Biology and Therapy.

Ischemia-reperfusion injury (IRI) is a complex pathophysiological process that is often characterized as a blood circulation disorder caused due to various factors (such as traumatic shock, surgery, organ transplantation, burn, and thrombus). Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. Theoretically, IRI can occur in various tissues and organs, including the kidney, liver, myocardium, and brain, among others. The advances made in research regarding restoring tissue perfusion in ischemic areas have been inadequate with regard to decreasing the mortality and infarct size associated with IRI. Hence, the clinical treatment of patients with severe IRI remains a thorny issue. Peroxisome proliferator-activated receptor γ (PPARγ) is a member of a superfamily of nuclear transcription factors activated by agonists and is a promising therapeutic target for ameliorating IRI. Therefore, this review focuses on the role of PPARγ in IRI. The protective effects of PPARγ, such as attenuating oxidative stress, inhibiting inflammatory responses, and antagonizing apoptosis, are described, envisaging certain therapeutic perspectives.

An introduction into the use of fabricated chimeric flaps in replantation surgery of digits

Since microsurgical finger replantations started to be successfully performed at the beginning of the 1960 s, there has been an evolution in the techniques for restoring blood flow to the amputated fingers. Initially, end-to-end anastomoses were performed. Later on, vascular grafts-predominantly vein interpositional grafts-were successfully used for difficult avulsion injuries. These vascular grafts were extended by microvascular flaps in the form of flow-through flaps in cases with simultaneous soft tissue loss. A further development of these techniques has been achieved by the replantation of amputated fingers with the help of fabricated chimeric flaps. The amputated finger is anastomosed microsurgically with a flap "in tabula" before the actual replantation. Only then is the fabricated chimera replanted as a construct. The latest development so far is heterotopic replantation with secondary replantation in the form a fabricated chimeric flap. By way of introduction, we describe three cases in which we have successfully applied this concept of fabricated chimeric flap surgery for orthotopic thumb replantations.

Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury

Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on the use of radical trapping antioxidants (RTAs), such as liproxstatin-1 (Lip-1). Hence, it is necessary to develop novel strategies to prevent cardiac IRI, thus improving the clinical outcome in patients with ischemic heart disease. The present review analyses the role of ferroptosis inhibition to prevent heart IRI, with special reference to Lip-1 as a promising drug in this clinicopathological context.

Allicin attenuates myocardial apoptosis, inflammation and mitochondrial injury during hypoxia-reoxygenation: an in vitro study

BackgroundMyocardial ischemia–reperfusion (IR) injury is a damage due to an initial reduction in blood flow to the heart, preventing it from receiving enough oxygen, and subsequent restoration of blood flow through the opening of an occluded coronary artery producing paradoxical harmful effects. The finding of new therapies to prevent IR is of utmost importance. Allicin is a compound isolated from garlic having the ability to prevent and cure different diseases, and a protective effect on the myocardium was also demonstrated. Therefore, the aim of this study was to evaluate the in vitro protective effect of Allicin against myocardial IR injury on cardiomyocytes.MethodsWe established an in vitro hypoxia-reoxygenation (HR) model of primary porcine cardiomyocytes to simulate myocardial IR injury. Primary porcine cardiomyocytes were extracted from Mini-musk swines (1 day old). After a period of adaptation of at least 2–3 days, cardiomyocytes in good condition were selected and randomly divided into control group (normal oxygen for 5 h), HR group (2 h of hypoxia/3 h of reoxygenation), and HR + Allicin group (hypoxia/reoxygenation + Allicin treatment).ResultsAfter the induction of hypoxia/reoxygenation, Allicin treatment enhanced the cell viability. Moreover, Allicin treatment resulted in a reduction of apoptosis from 13.5 ± 1.2% to 6.11 ± 0.15% compared with the HR group (p < 0.05), and the apoptosis related proteins were regulated as well, with a decreased expression of Bax, cleaved caspase-3 and cytosolic cytochrome C and an increase in Bcl-2 expression in the HR + Allicin group (all p < 0.01). Pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor alpha were down-regulated by the treatment with Allicin (both p < 0.01). In addition, it significantly decreased intracellular reactive oxygen species generation (p < 0.01) and reduced the loss of mitochondrial membrane potential (p < 0.01). Furthermore, the expression of PPARγ coactivator-1α and endothelial nitric oxide synthase was up-regulated (both p < 0.01), while the expression of Endothelin-1, hypoxia inducing factor-1α and transforming growth factor beta was down-regulated (all p < 0.01) by Allicin treatment.ConclusionsThese results suggested that Allicin protected the cardiomyocytes against HR damage by reducing apoptosis, inflammation and mitochondrial injury, thus providing a basis for its potential use in the treatment of myocardial IR.

Improved Functional Outcome After Peripheral Nerve Stimulation of the Impaired Forelimb Post-stroke.

Lack of blood flow to the brain, i.e., ischemic stroke, results in loss of nerve cells and therefore loss of function in the effected brain regions. There is no effective treatment to improve lost function except restoring blood flow within the first several hours. Rehabilitation strategies are widely used with limited success. The purpose of this study was to examine the effect of electrical stimulation on the impaired upper extremity to improve functional recovery after stroke. We developed a rodent model using an electrode cuff implant onto a single peripheral nerve (median nerve) of the paretic forelimb and applied daily electrical stimulation. The skilled forelimb reaching test was used to evaluate functional outcome after stroke and electrical stimulation. Anterograde axonal tracing from layer V pyramidal neurons with biotinylated dextran amine was done to evaluate the formation of new neuronal connections from the contralesional cortex to the deafferented spinal cord. Rats receiving electrical stimulation on the median nerve showed significant improvement in the skilled forelimb reaching test in comparison with stroke only and stroke with sham stimulation. Rats that received electrical stimulation also exhibited significant improvement in the latency to initiate adhesive removal from the impaired forelimb, indicating better sensory recovery. Furthermore, axonal tracing analysis showed a significant higher midline fiber crossing index in the cervical spinal cord of rats receiving electrical stimulation. Our results indicate that direct peripheral nerve stimulation leads to improved sensorimotor recovery in the stroke-impaired forelimb, and may be a useful approach to improve post-stroke deficits in human patients.

Nanoassemblies of Disulfide-Bridged Bile Acid Dimers as Therapeutics Agents for Hepatic Ischemia/Reperfusion Injury.

Ischemia/reperfusion (IR) injury is induced by the restoration of blood flow to the prolonged ischemic tissues and is considered as the paradoxical exacerbation of ischemic damages. A large amount of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) produced immediately after reperfusion induces oxidative stress, which plays an essential role in the pathogenesis of IR injury. It is therefore critical to suppress oxidative stress for the prevention and treatment of IR injury. Ursodeoxycholic acid (UDCA), one of the tertiary bile acids, promotes the generation of antioxidant glutathione (GSH) and also exerts hepatoprotective, cytoprotective, and antiapoptotic effects. However, the clinical uses of UDCA are limited mainly by its poor water solubility and low bioavailability. In this study, by exploiting the concept of self-assembling disulfide-bridged dimeric prodrugs, we developed a disulfide-bridged UDCA dimer (ssUDCA) as a therapeutic agent of hepatic IR injury. ssUDCA could self-assemble into stable nanospheres under aqueous conditions, scavenge H2O2, and exert anti-inflammatory and antiapoptotic activities. In a mouse model of hepatic IR injury, ssUDCA (5 mg/kg) significantly alleviated the IR injury by suppressing ROS production and inhibiting proinflammatory cytokines. Therefore, our findings offer a promising strategy for the effective treatment of hepatic IR injury and also provide deep insights into the impact of disulfide-bridged UDCA nanoassemblies in pharmaceutical applications.

POS-073 Rapid Changes in the Mitochondrial Membrane Potential of Proximal Tubular Cells At the Start of Ischemia/Reperfusion Injury

Renal Ischemia/reperfusion injury (IRI) is characterized by the restriction of blood supply, followed by restoration of blood flow and re-oxygenation. Reperfusion itself paradoxically exacerbates tissue injury, threatening the function, and viability of the organ. IRI is usually associated with a variety of homeostatic changes that involve reduced energetics, and oxidative processes that contribute to mitochondrial dysfunction. Depending on the severity and duration of the injury, this condition can be reversed completely to reinstate normal function or be sustained for the subsequent loss of function.

EVALUATION OF THE CARDIOPROTECTIVE EFFECT OF MANGIFERIN IN AN EXPERIMENTAL MODEL OF ISCHEMIA REPERFUSION INJURY

Objective: The injurious effects of restoration of coronary blood flow following myocardial infarction is a major concern as reperfusion predisposes to myocardial injury. Mangiferin is a polyphenolic antioxidant present in the bark, fruits, roots and leaves of Mangifera indica Linn (Anacardiaceae). It is known to modulate biological targets in inflammation &amp; oxidative stress. It also possesses anti-oxidant, anti-apoptotic; anti-atherogenic and anti-diabetic actions. Hence, we hypothesized that the anti-oxidative, anti-inflammatory, and anti-apoptotic effects of mangiferin may also be involved in the prevention of IR injury. Design and method: Male albino Wistar rats were divided into four groups i.e. sham, IR-control, Mangiferin-40 + IR and Mangiferin 40 per se. Mangiferin was administered at a dose of 40 mg/kg, intraperitoneally for 15 days. On the 15th day, myocardial IR injury was induced by occluding the left anterior descending coronary artery for 45 minutes followed by reperfusion for 60 minutes. At the end of the surgical procedure, the rats were sacrificed, the hearts excised and processed. Results: IR-control rats showed significant cardiac dysfunction along with a raised serum cardiac injury markers, and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats showed myocardial necrosis, edema and inflammatory cell infiltration. Pre-treatment with mangiferin significantly suppressed myocardial oxidative damage, maintained membrane integrity, and attenuated the levels of pro-inflammatory cytokines, pro-apoptotic proteins and TGF-beta. Additionally, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. Conclusions: Mangiferin ameliorates myocardial IR injury by alleviating oxidative stress mediated apoptosis and modulating MAPK mediated inflammation.

The effect of astaxanthin on testicular torsion-detorsion injury in rats – Detailed morphometric evaluation of histological sections

Testicular torsion is one of the conditions of the acute scrotum that requires immediate surgical intervention. If not recognized at time, it can result of ischemic injuries and testicular loss. Restoration of blood flow is essential to save ischemic tissue, but reperfusion itself paradoxically causes further damage. Seaweed and sponges are considered to be the richest source of bioactive compounds that have antioxidant activity. The antioxidant activity of astaxanthin is 10 times higher than zeaxanthin, lutein, canthaxanthin, β-carotene and 100 times higher than α-tocopherol. Since to date there is no drug given to patients with torsion-detorsion testicular injury, we have investigated the effect of this powerful antioxidant. The aim of this study was to determine the effect of astaxanthin (ASX) on testicular torsion-detorsion injury in rats. Thirty-two male Fischer prepubertal rats were divided into 4 groups of 8 individuals. Group 1 underwent sham surgery to determine basal values for histological evaluation. In group 2 (torsion-detorsion group), right testis was twisted at 720° for 90min. After 90min of reperfusion, the testis was removed. Astaxanthin was administered intraperitoneally at the time of detorsion (group 3) and 45min after detorsion (group 4) in the treatment groups. Using software ImageJ®, histological morphometric values were measured. MSTD (mean seminiferous tubule diameter) values increase statistically significantly in ASX groups compared to T/D group. MSLD (mean seminiferous lumen diameter) value was statistically significantly lower in the ASX group 3 compared to the T/D group. Epithelial height was statistically significantly higher in ASX groups compared to the T/D group. Tubular area is statistically significantly higher in ASX group 4, while the luminal area is statistically significantly lower in the ASX group 3 compared to the T/D group. Johnsen score was statistically significantly higher in the ASX groups compared to the T/D group. This is the first scientific paper to study the effects of a single powerful antioxidant on all morphometric parameters. In previous scientific papers, scientists have mainly measured MSTD and the Johnsen score. By measuring all histological morphometric parameters (mean seminiferous tubule diameter, mean seminiferous lumen diameter, epithelial height, tubular area, luminal area, Johnsen score) it can be concluded that astaxanthin has a favorable effect comparing the treated groups to untreated group.

Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3.

[Figure: see text].

Macrophage–Hypoxia-Inducible Factor-1α Signaling in Carotid Artery Stenosis

Macrophages play crucial and diverse roles in the pathogenesis of inflammatory vascular diseases. Macrophages are the principal innate immune cells recruited to arterial walls to govern vascular homeostasis by modulating the proliferation of vascular smooth muscle cells, the reorganization of extracellular matrix components, the elimination of dead cells, and the restoration of normal blood flow. However, chronic sterile inflammation within the arterial walls draws inflammatory macrophages into intimal/neointimal regions that may contribute to disease pathogenesis. In this context, the accumulation and aberrant activation of macrophages in the neointimal regions govern the progression of inflammatory arterial wall diseases. Herein, we report that myeloid-hypoxia-inducible factor-1α (HIF1α) deficiency attenuates vascular smooth muscle cells and macrophage abundance in stenotic arteries and abrogates carotid neointima formation invivo. The integrated transcriptomics, Gene Set Enrichment Analysis, metabolomics, and target gene evaluation showed that HIF1α represses oxidative phosphorylation, tricarboxylic acid cycle, fatty acid metabolism, and c-MYC signaling pathways while promoting inflammatory, glycolytic, hypoxia response gene expression in stenotic artery macrophages. At the molecular level, proinflammatory agents utilized STAT3 signaling pathways to elevate HIF1α expression in macrophages. Collectively, this study uncovers that macrophage-HIF1α deficiency restrains the pathogenesis of carotid artery stenosis by rewiring inflammatory and metabolic signaling pathways in macrophages.