Macrophage Polarization as a Novel Therapeutic Target for Endovascular Intervention in Peripheral Artery Disease.
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ABSTRACT:
SUBMITTER: Tan RP
PROVIDER: S-EPMC8385566 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Atherosclerotic occlusions decrease blood flow to the lower limbs, causing ischemia and tissue loss in patients with peripheral artery disease (PAD). No effective medical therapies are currently available to induce angiogenesis and promote perfusion recovery in patients with severe PAD. Clinical trials aimed at inducing vascular endothelial growth factor (VEGF)-A levels, a potent proangiogenic growth factor to induce angiogenesis, and perfusion recovery were not successful. Alternate splicing in the exon-8 of VEGF-A results in the formation of VEGFxxxa (VEGF165a) and VEGFxxxb (VEGF165b) isoforms with existing literature focusing on VEGF165b's role in inhibiting vascular endothelial growth factor receptor 2-dependent angiogenesis. However, we have recently shown that VEGF165b blocks VEGF-A-induced endothelial vascular endothelial growth factor receptor 1 (VEGFR1) activation in ischemic muscle to impair perfusion recovery. Because macrophage-secreted VEGF165b has been shown to decrease angiogenesis in peripheral artery disease, and macrophages were well known to play important roles in regulating ischemic muscle vascular remodeling, we examined the role of VEGF165b in regulating macrophage function in PAD. METHODS:Femoral artery ligation and resection were used as an in vivo preclinical PAD model, and hypoxia serum starvation was used as an in vitro model for PAD. Experiments including laser-Doppler perfusion imaging, adoptive cell transfer to ischemic muscle, immunoblot analysis, ELISAs, immunostainings, flow cytometry, quantitative polymerase chain reaction analysis, and RNA sequencing were performed to determine a role of VEGF165b in regulating macrophage phenotype and function in PAD. RESULTS:First, we found increased VEGF165b expression with increased M1-like macrophages in PAD versus non-PAD (controls) muscle biopsies. Next, using in vitro hypoxia serum starvation, in vivo pre clinical PAD models, and adoptive transfer of VEGF165b-expressing bone marrow-derived macrophages or VEGFR1+/- bone marrow-derived macrophages (M1-like phenotype), we demonstrate that VEGF165b inhibits VEGFR1 activation to induce an M1-like phenotype that impairs ischemic muscle neovascularization. Subsequently, we found S100A8/S100A9 as VEGFR1 downstream regulators of macrophage polarization by RNA-Seq analysis of hypoxia serum starvation-VEGFR1+/+ versus hypoxia serum starvation-VEGFR1+/- bone marrow-derived macrophages. CONCLUSIONS:In our current study, we demonstrate that increased VEGF165b expression in macrophages induces an antiangiogenic M1-like phenotype that directly impairs angiogenesis. VEGFR1 inhibition by VEGF165b results in S100A8/S100A9-mediated calcium influx to induce an M1-like phenotype that impairs ischemic muscle revascularization and perfusion recovery.
| S-EPMC6322929 | biostudies-literature
Project description:A total of 102 patients were randomized to either mono-therapy with simvastatin (40 mg daily) or triple-therapy with simvastatin (40 mg daily), extended-release niacin (1500 mg daily), and ezetimibe (10 mg daily). MRI was performed at baseline and 6, 12, and 24 months. SFA wall, lumen, and total vessel volumes were quantified. MRI-derived SFA parameters and lipids were analyzed with multilevel models and nonparametric tests, respectively.Baseline characteristics did not differ between mono and triple-therapy groups, except for ethnicity (p = 0.02). SFA wall, lumen, and total vessel volumes increased non-significantly for both groups between baseline and 24-months. Non-high-density lipoprotein cholesterol was significantly reduced at 12 months with triple-therapy compared with mono-therapy (p = 0.01).No significant differences were observed between mono-therapy using simvastatin and triple-therapy with simvastatin, extended-release niacin, and ezetimibe for 24-month changes in SFA wall, lumen, and total vessel volumes.NCT00687076; Link: http://clinicaltrials.gov/ct2/show/NCT00687076.
| S-EPMC4545656 | biostudies-literature
Project description:BackgroundTo date, few data have been reported on clinical outcomes following interventions in elderly populations with acute basilar artery occlusion. Using data from the Endovascular Treatment for Acute Basilar Artery Occlusion Study (BASILAR), we evaluated the efficacy and safety of intervention and determined predictors of outcomes among elderly patients in China.MethodsPatients from January 2014 to May 2019 were dichotomized into elderly (75 years or older) and nonelderly patients (under 75 years). Pearson's Chi-square test and multivariate logistic regression were performed to assess 90-day favorable functional outcome (defined as a modified Rankin scale score of 0-3), mortality and symptomatic intracranial hemorrhage between intervention and conservative cohorts in elderly patients.ResultsAmong the 829 patients in the BASILAR, 182 patients aged 75 years or older were analyzed. These patients were divided into intervention (127 patients) and conservative (55 patients) cohorts. Compared with the conservative cohort, the intervention cohort presented more frequently with a favorable functional outcome (28.3% versus 12.7%; p = 0.023) and with a decreased mortality (54.3% versus 76.4%; p = 0.005). There was no difference in symptomatic intracranial hemorrhage (4.7% versus 0, p = 0.235). Multivariate analysis indicated that intervention was associated with favorable functional outcome (adjusted odds ratio, 0.262; 95% confidence interval, 0.088-0.778, p = 0.016) and lower mortality (adjusted odds ratio, 0.257; 95% confidence interval, 0.109-0.606, p = 0.002). In the intervention cohort, initial National Institutes of Health Stroke Scale (NIHSS) score and occlusion site were associated with functional outcome, and initial NIHSS score and recanalization were associated with mortality.ConclusionsAlthough the overall outcome following intervention was worse with age, intervention was more effective and safer than conservative treatment for elderly Chinese patients with basilar artery occlusion. Predictors of desirable outcome in elderly patients undergoing intervention included lower initial NIHSS score, occlusion site and successful recanalization.Clinical Trial Registration-URL: http://www.chictr.org. Unique identifier: ChiCTR-1800014759.
| S-EPMC8047973 | biostudies-literature
Project description:Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.
| S-EPMC3760002 | biostudies-literature
Project description:Peripheral arterial disease (PAD) is a major health care problem. There have been limited advances in medical therapies, and a huge burden of symptomatic patients with intermittent claudication and critical limb ischemia who have limited treatment options. Angiogenesis is the growth and proliferation of blood vessels from existing vasculature. For approximately 2 decades, "therapeutic angiogenesis" has been studied as an investigational approach to treat patients with symptomatic PAD. Despite literally hundreds of positive preclinical studies, results from human clinical studies thus far have been disappointing. Here we present an overview of where the field of therapeutic angiogenesis stands today and examine lessons learned from previously conducted clinical trials. The objective is not to second-guess past efforts but to place the lessons in perspective to allow for trial success in the future to improve agent development, trial design, and ultimately, clinical outcomes for new therapeutics for PAD.
| S-EPMC5802410 | biostudies-literature
Project description:Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and conveys a significant health burden globally. Critical limb ischaemia encompasses the most severe consequence of PAD. Our previous studies indicate that microRNA let-7g prevents atherosclerosis and improves endothelial functions. This study aimed to investigate whether and how let-7g therapy may improve blood flow to ischaemic limbs. The present study shows that let-7g has multiple pro-angiogenic effects on mouse ischaemic limb model and could be a potential therapeutic agent for PAD. Mice receiving intramuscular injection of let-7g had more neovascularization, better local perfusion and increased recruitment of endothelial progenitor cells after hindlimb ischaemia. The therapeutic effects of let-7g's on angiogenesis are mediated by multiple regulatory machinery. First, let-7g increased expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR-2) through targeting their upstream regulators HIF-3α and TP53. In addition, let-7g affected the splicing factor SC35 which subsequently enhanced the alternative splicing of VEGF-A from the anti-angiogenic isoform VEGF-A165b towards the pro-angiogenic isoform VEGF-A164a . The pleiotropic effects of let-7g on angiogenesis imply that let-7g may possess a therapeutic potential in ischaemic diseases.
| S-EPMC5323674 | biostudies-literature
Project description:A patient with occlusion of the left superficial femoral artery (SFA) underwent endovascular intervention. Six-month follow-up angiography revealed aneurysmal dilatation of the previously stented artery. This finding may be a result of maladaptive vascular remodeling or arterial injury resulting in aneurysmal dilatation secondary to subintimal crossing, atherectomy, and paclitaxel therapies. (Level of Difficulty: Beginner.).
| S-EPMC8311142 | biostudies-literature
Project description:Coronary artery disease (CAD) is characterized by insufficient vasculogenic response to ischemia, which is typically accompanied by dysfunction of endothelial outgrowth cells (EOCs). CXC chemokine receptor 7 (CXCR7) is a key modulator of the neovascularization of EOCs to perfusion defect area. However, the mechanism underlying the role of EOCs in CAD-related abnormal vasculogenesis is still not clear. Here, we investigated the alteration of EOCs-related vasculogenic capacity in patients with CAD and its potential mechanism. Compared with EOCs isolated from healthy subjects, EOCs from CAD patients showed an impaired vasculogenic function in vitro. CXCR7 expression of EOCs from CAD patients was downregulated. Meanwhile, the phosphorylation of extracellular signal-regulated kinase (ERK), downstream of CXCR7 signaling, was also reduced. CXCR7 expression introduced by adenovirus increased the phosphorylation of ERK, which was parallel to improved function of EOCs. The enhanced adhesion and vasculogenesis of EOCs can be blocked by short interfering RNA (siRNA) against CXCR7 and ERK inhibitor PD098059. Therefore, our study demonstrates that the upregulation of CXCR7 signaling contributes to increased vasculogenic capacity of EOCs from CAD patients, indicating that CXCR7 signaling may be a novel therapeutic vasculogenic target for CAD.
| S-EPMC5017667 | biostudies-literature
Project description:Macrophages are terminally differentiated cells of the mononuclear phagocyte system that also encompasses dendritic cells, circulating blood monocytes, and committed myeloid progenitor cells in the bone marrow. Both macrophages and their monocytic precursors can change their functional state in response to microenvironmental cues exhibiting a marked heterogeneity. However, there are still uncertainties regarding distinct expression patterns of surface markers that clearly define macrophage subsets, particularly in the case of human macrophages. In addition to their tissue distribution, macrophages can be functionally polarized into M1 (proinflammatory) and M2 (alternatively activated) as well as regulatory cells in response to both exogenous infections and solid tumors as well as by systems biology approaches.
| S-EPMC3236674 | biostudies-other
Project description:Atherosclerosis is the leading cause of morbidity and mortality in the Western world. Peripheral artery disease (PAD) has been less studied then coronary artery disease but is nearly as common. PAD impairs blood flow to the leg(s) and causes functional impairment, leg pain, and amputation. The last drug approved for PAD was in 1999. Blood flow to leg proceeds through one major artery and in PAD total occlusions in the course of that vessel are common. Thus, the extent of new blood vessel growth determines a patients' clinical course. Promoting the growth of new blood vessels (therapeutic angiogenesis) was a major goal of therapy. Results from studies using cytokine growth factors have shown disappointing results. Using clinical and preclinical studies, our laboratory has identified several novel therapeutic approaches. One, a modulator of innate immunity, will be reviewed as an approach that has the potential to create new therapies for PAD.
| S-EPMC5216482 | biostudies-literature