Collateral Vessel Formation Research Articles

Recognizing Moyamoya Disease in a Soldier With Recurrent Cerebrovascular Symptoms.

Moyamoya is a rare and progressive cerebrovascular disease involving collateral small vessel formation associated with intracranial artery narrowing. It is a disease that frequently presents with stroke and transient ischemic attacks and has potential to affect our active duty service members and their families with its bimodal age of onset of 10 and 40. This case report describes a soldier with moyamoya whose diagnosis was unrecognized for over a year after seeing multiple medical providers regarding his symptoms. The goal of this case report is to raise vigilance for this disease as it can cause significant morbidity and mortality with mental decline, recurrent strokes, and death without timely surgery.

Moyamoya disease and syndrome: a review.

Moyamoya disease is a chronic occlusive cerebrovascular disease that is non-inflammatory and non-atherosclerotic. It is characterized by endothelial hyperplasia and fibrosis of the intracranial portion of the carotid artery and its proximal branches, leading to progressive stenosis and occlusion, often clinically manifesting as ischemic or hemorrhagic stroke with high rates of morbidity and mortality. On cerebral angiography, the formation of collateral vessels has the appearance of a puff of smoke (moyamoya in Japanese), which became more conspicuous with the refinement of modern imaging techniques. When there is associated disease, it is known as moyamoya syndrome. Treatments are currently limited, although surgical revascularization may prevent ischemic events and preserve quality of life. In this review, we summarize recent advances in moyamoya disease, covering aspects of epidemiology, etiology, presentation, imaging, and treatment strategies.

Current Concepts and Future Perspectives of Stem Cell Therapy in Peripheral Arterial Disease

Some advanced stage peripheral arterial disease (PAD) patients will not eligible for revascularization strategies. From the last two decades stem cell therapy (SCT) has been explored as an alternative therapy for no option advanced stage PAD patients. Therapeutic motif of this novel therapy is to promote the collateral vessel formation that will improve the blood flow to ischemic leg that in turn can prevent major amputations. This mini review provides the brief outline of the use of autologous and allogeneic SCT for the treatment of advanced stage PAD

Ablation of DUSP4 Exacerbates Blood Flow Reperfusion in Diabetic Limb

Collateral vessel formation, a normal response to artery occlusion, is impaired in patients with diabetes, rendering the tissue downstream more susceptible to critical ischemia. Thus, understanding of the mechanisms induced by diabetes on reduced collateral vessel formation may offer new therapeutic perspectives to prevent amputation. Our laboratory has discovered that diabetes decreased the expression of DUSP4, which was associated with elevated inflammation and vascular dysfunction.

Satellite Cell Expression of RAGE (Receptor for Advanced Glycation end Products) Is Important for Collateral Vessel Formation.

BackgroundThe growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is RAGE (receptor for advanced glycation end products). This study sought to determine the cellular source of RAGE in the ischemic hind limb and the role of RAGE signaling in this cell type.Methods and ResultsUsing a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. Although wild‐type satellite cells increased tumor necrosis factor‐α and monocyte chemoattractant protein‐1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand high‐mobility group box 1. Furthermore, encapsulated wild‐type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification, but RAGE knockout satellite cells provided no improvement over empty capsules.ConclusionsThus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions.

Preliminary study of hemodynamics of iliac venous compression syndrome using magnetic resonance imaging

ObjectiveIn clinical practice, the degree of iliac vein stenosis has often been inconsistent with the symptoms of chronic venous disease (CVD). To the best of our knowledge, no clinical studies have evaluated the hemodynamic changes associated with iliac vein stenosis. Magnetic resonance imaging (MRI) can noninvasively provide hemodynamic information. In the present study, we assessed the degree of stenosis associated with iliac venous compression syndrome and the relationships between iliac venous compression syndrome-induced, MRI-determined hemodynamic changes and lower limb symptoms. MethodsStenosis severity, the presence of collateral vessels, and flow rate (FR) differences between the common and external iliac veins secondary to iliac vein stenosis were measured using MRI in 69 patients with CVD. Villalta scores were used as a measure of symptom severity for all patients, and the percentage of change in the Villalta score was used as a measure of symptom improvement for the patients who had received iliac vein stents. Symptom severity for all patients, a subgroup of patients with iliac vein compression (affected limbs), and a group of patients with unilateral iliac vein compression treated with stents was correlated with stenosis, differences in the external and common iliac vein FRs (<0-mL/s group, indicating stenosis-induced decreased common iliac vein flow, and ≥0-mL/s group), and stenosis-induced collateral vessel formation. ResultsIliac vein stenosis severity and FR differences in all affected limbs were correlated with the Villalta scores of the affected limbs (stenosis: r = 0.38, P < .001, n = 95; FR difference: r = −0.44, P < .001). In the unilateral compression subgroup, stenosis severity, FR differences, and the presence of collateral vessels were not associated with significant changes in contralateral symptoms. In the endovascular treatment subgroup, both lower limbs exhibited significant improvement after stent implantation (affected limb symptom remission, 64.6% ± 18.2%, n = 15; contralateral limb symptom remission, 49.1% ± 29.1%, n = 11). The rate of symptom remission was greater for patients with decreased iliac vein flow in the affected limbs (<0-mL/s group: 74.6% ± 16.4%, n = 7; ≥0-mL/s group: 52.2% ± 16.6%, n = 6; P = .032). ConclusionsIliac vein stenosis, the presence of collateral vessels, and decreased FRs due to stenosis correlated significantly with lower limb symptom severity. Endovascular treatment yielded good outcomes in patients with stenosis >50%. A decreased iliac venous FR could indicate a better response to stent implantation and could be used in the diagnosis and guiding decisions to treat iliac venous compression.

Disease-modifying effects of ranibizumab for central retinal vein occlusion

PurposeTo identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes.MethodsA post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy.ResultsAt 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: − 1.17 [sham], − 2.37 [ranibizumab 0.3 mg], − 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups.ConclusionsRanibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO.

S1852 Colonic Varices Due to Alcoholic Cirrhosis

Introduction: Ectopic varices (all varices outside the gastroesophageal region) account for 1-5% of all variceal bleeding episodes. Specifically, colon varices are rare, as incidence of colonic varices, irrespective of etiology, is around 0.07%. If colonic varices bleed, treatment is urgent, as delay in treatment can potentially be fatal. Case description/methods: A 55 year old male with a past medical history of complicated diverticulitis status post open sigmoidectomy and heavy alcohol abuse with history of deliriums tremens who was admitted due to having hematochezia with bowel movements for two days. He denied any hematemesis, abdominal pain, melena or NSAID use. Patient was hypotensive on arrival to the ED with MAPs in the 40s. On physical exam, scleral icterus along asterixis and tremors in his hands were noted. CTA Abdomen and Pelvis showed no signs of active gastrointestinal bleeding with signs of hepatic cirrhosis with extensive esophageal, gastric varices, and descending colon varices. Patient had two more episodes of hematochezia in the ED. Patient was given 2 units of emergent blood in the ED to help stabilize his blood pressure. Patient did not have a diagnosis of cirrhosis prior to presentation. He admitted to drinking a six pack of beer daily for the past thirty years. Last colonoscopy was five years ago which showed tubular adenomatous polyps in the rectum and ascending colon. Diverticulosis was also present in the ascending colon. Patient had EGD performed which showed some mild esophagitis and some portal hypertensive gastropathy (PHG) located in the antrum, body and fundus. Flexible sigmoidoscopy was then performed which showed a large amount of fresh and old blood coming from a sigmoid varix at 25 cm located in the sigmoid colon. Hemostasis was achieved with using a Bear claw clip (Figure 1). Discussion: Colonic varices can develop secondary to portal hypertension, congenital anomalies in venous outflow, mesenteric or splenic vein thrombosis, congestive heart failure, or formation of collateral vessels from previous abdominal surgeries. Patients with suspected bleeding colonic varices need immediate assessment, resuscitation, and hemodynamic stabilization. There are no evidence based guidelines for treatment for bleeding colonic varices, but options include medical, endoscopic, interventional radiological and surgical modalities.Figure 1.: Bear claw clip was used to achieve hemostasis.

The effect of atherogenic plasma index on collateral development in patients with chronic coronary total occlusion

Aim: To demonstrate the correlation between coronary collateral circulation (CCC) and atherogenic plasma index (AIP), one of the factors associated with the formation of collateral vessels. Methods: Hospital records of patients with chronic total occlusion (100% stenosis) in at least one coronary artery were evaluated. Triglycerides, HDL level, triglyceride/HDL ratio and atherogenic plasma index before coronary angiography were assessed for the 451 patients who met the study criteria. Results: Comparison of the two groups in terms of laboratory findings showed that triglyceride/HDL ratio (5.04±3.13 vs 3.56±2.12, p<0.001) and AIP (0.63±0.25 vs 0.48±0.25, p<0.001) were higher with statistical significance in the weak collateral group. The ROC analysis revealed an association between weak collateral formation and atherogenic plasma index with 64.7% sensitivity and 66.2% specificity using a cut-off value of 0.58 for AIP. Accordingly, low AIP was found to be an independent predictor of good collateral artery formation. Conclusion: This study suggests that a high atherogenic plasma index may be an independent factor associated with poor collateral formation.

Experimental animal models for the study of moyamoya disease.

Moyamoya disease is a rare disorder of the cerebrovascular system affecting individuals in a bimodal age distribution and is characterized by progressive vascular stenosis of the bilateral supraclinoid internal carotid arteries with compensatory formation of collateral vessels at the base of the brain. Despite the disease's initial description in the literature in 1957, little progress has been made in the development of medical and surgical therapeutics due to, in no small part, the lack of effective experimental animal models. Currently, there is a poor understanding of the pathophysiological mechanisms behind the development of the moyamoya vasculopathies. Since the description of a genetic association between moyamoya disease, few studies have investigated the impact of genetic manipulation on the development of an animal model for experimentation. To date, no one model recapitulates the precise phenotype of the moyamoya vasculopathies, although development of an appropriate model would allow for an in-depth investigation into the pathological mechanisms underlying the disease. In this review, the authors discuss the immunological, mechanical, and genetic methods used to develop moyamoya experimental models, as well as future perspectives.

Transcriptome-wide analysis of intracranial artery in patients with moyamoya disease showing upregulation of immune response, and downregulation of oxidative phosphorylation and DNA repair.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive occlusion of the internal carotid artery and the secondary formation of collateral vessels. Patients with MMD have ischemic attacks or intracranial bleeding, but the disease pathophysiology remains unknown. In this study, the authors aimed to identify a gene expression profile specific to the intracranial artery in MMD. This was a single-center, prospectively sampled, retrospective cohort study. Microsamples of the middle cerebral artery (MCA) were collected from patients with MMD (n = 11) and from control patients (n = 9). Using microarray techniques, transcriptome-wide analysis was performed. Comparison of MCA gene expression between patients with MMD and control patients detected 62 and 26 genes whose expression was significantly (p < 0.001 and fold change > 2) up- or downregulated, respectively, in the MCA of MMD. Gene set enrichment analysis of genes expressed in the MCA of patients with MMD revealed positive correlations with genes involved in antigen processing and presentation, the dendritic cell pathway, cytokine pathway, and interleukin-12 pathway, and negative correlations with genes involved in oxidative phosphorylation and DNA repair. Microarray analysis was validated by quantitative polymerase chain reaction. Transcriptome-wide analysis showed upregulation of genes for immune responses and downregulation of genes for DNA repair and oxidative phosphorylation within the intracranial artery of patients with MMD. These findings may represent clues to the pathophysiology of MMD.

Feasibility of using the homologous parietal peritoneum as a vascular substitute for venous reconstruction during abdominal surgery: An animal model

BackgroundThe interest in vascular substitutes has recently increased. We evaluated the feasibility of using a homologous parietal peritoneum as a vascular substitute for venous reconstruction during abdominal surgery. MethodsThe inferior vena cava was replaced with a homologous parietal peritoneum after cross-linking with glutaraldehyde in 36 rabbits. At 7, 14, and 28 days, the patency rate, outer and inner graft diameters, histology, and immunohistochemistry were evaluated. ResultsBoth the 7- and 14-day groups maintained vascular patency. Vascular patency was maintained in 3 rabbits in the 28-day group. The inner diameters of the anastomotic sites were 6.23 ± 0.18, 5.64 ± 0.16, and 2.34 ± 0.21 mm in the 7-day, 14-day, and 28-day groups, respectively. The midpoint inner diameters of the homologous parietal peritoneum grafts were 624 ± 0.46, 5.74 ± 0.26, and 2.14 ± 0.28 mm in each group, respectively. Endothelial cell proliferation on the homologous parietal peritoneum graft surfaces in all groups was based on the histological findings from the first group. Multiple neovascularizations of the homologous parietal peritoneum graft were found in the 14- and 28-day groups, indicating neo-media formation. Acute inflammation appeared to progress to the entire layer of the homologous parietal peritoneum graft without an intraluminal thrombus, but the graft was patent in the 14-day group. In the 28-day group, 6 rabbits showed near-total occlusion and a thrombus formed in the homologous parietal peritoneum graft at the anastomosis site with severe stricture; however, the rabbits were alive and had collateral vessel formation. ConclusionUsing homologous parietal peritoneum is feasible for venous reconstruction in abdominal surgery.

Feasibility of using the homologous parietal peritoneum as a vascular substitute for venous reconstruction during abdominal surgery: An animal model

The interest in vascular substitutes has recently increased. We evaluated the feasibility of using a homologous parietal peritoneum (HPP) as a vascular substitute for venous reconstruction during abdominal surgery. The inferior vena cava was replaced with an HPP after cross-linking with glutaraldehyde in 15 rabbits. At 7, 14, and 28 days, the patency rate, outer and inner graft diameters, histology, and immunohistochemistry were evaluated. Both the 7- and 14-day groups maintained vascular patency. Vascular patency was maintained in three rabbits in the 28-day group. The inner diameters of the anastomotic sites were 6.12 ± 0.20 mm, 5.63 ± 0.14 mm, and 2.22 ± 0.23 mm in the 7-day, 14-day, and 28-day groups, respectively. The mid-point inner diameters of the HPP grafts were 6.21 ± 0.13 mm, 5.82 ± 0.16 mm, and 2.12 ± 0.24 mm in each group, respectively. Endothelial cell proliferation on the HPP graft surfaces in all groups was based on the histological findings from the first group. Multiple neo-vascularization of the HPP graft were found in the 14- and 28-day groups, indicating neo-media formation. Acute inflammation appeared to progress to the entire layer of the HPP graft without an intraluminal thrombus, but the graft was patent in the 14-day group. In the 28-day group, two rabbits showed near-total occlusion and a thrombus formed in the HPP graft at the anastomosis site with severe stricture; however, the rabbits were alive and had collateral vessel formation. Use of the HPP is feasible for venous reconstruction in abdominal surgery.

Encephaloduroarteriosynangiosis (EDAS) treatment of moyamoya syndrome: evaluation by computed tomography perfusion imaging

To explore the value of computed tomography perfusion (CTP) imaging for evaluating the efficacy of encephaloduroarteriosynangiosis (EDAS) treatment of moyamoya syndrome (MMS). Forty-three patients with MMS (48 hemispheres) who received EDAS treatment were examined using CTP and DSA before and after surgery. CTP of the ipsilateral cortex, contralateral mirror area, and pons region were measured, and the relative cerebral blood flow (rCBF) and volume (rCBV), mean transit time (rMTT), and time-to-peak (rTTP) were calculated. Based on postoperative DSA, 48 hemispheres were apportioned to two groups based on rich (grades 2, 3) or poor (grades 0, 1) collateral vessel formation, and the pre- and post-operative differences in perfusion changes were compared. The association between clinical outcome, CTP, and the degree of DSA collateral vessels was explored. rCBF and rMTT significantly improved in both the poor and rich collateral vessel formation groups (n = 21 and 27, respectively), while rTTP significantly improved only in the latter. Postoperative CTP improved in the rich and the grade 1 collateral vessel groups (p < 0.01). The clinical improvement was consistent with the improvement of CTP (p = 0.07), but less consistent with the degree of collateral angiogenesis (p = 0.003). CTP can quantitatively evaluate the improvement of brain tissue perfusion in the operated area after EDAS. Brain tissue perfusion in operated areas improved regardless of postoperative rich or poor collateral vessel formation observed via DSA. A significant improvement in rTTP in the operated area may indicate the formation of abundant collateral vessels. • CTP showed that brain tissue perfusion in the operated area after EDAS improved regardless of rich or poor collateral vessel formation observed via DSA. • Significant improvement of rTTP in the operated area may indicate the formation of abundant collateral vessels.

Effect of intravitreal dexamethasone implant versus ranibizumab on vessel density in branch retinal vein occlusion.

This study aimed to compare the effect of intravitreal dexamethasone implant with that of ranibizumab on vessel density (VD) in eyes with branch retinal vein occlusion (BRVO). Sixty-three eyes of 63 patients with superotemporal BRVO treated either with intravitreal dexamethasone implant (DEX group, n = 31) or ranibizumab (RNB group, n = 32) were prospectively enrolled. Swept-source optical coherence tomography angiography 6 × 6 mm scans of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in all eyes were analyzed. The mean baseline VD of the SCP and the DCP was similar between groups in all quadrants (p > 0.05 for all). At 12 months, the VD of the SCP in the parafoveal superior and temporal quadrants was significantly higher in the RNB group than in the DEX group (p = 0.002 and p = 0.001, respectively). The VD of the DCP in the parafoveal temporal, nasal, and superior quadrants was significantly higher in the RNB group than in the DEX group (p < 0.05 for all). Further, there was a statistically significant positive correlation between the improvement of visual acuity and increased VD of the SCP and the DCP in the parafoveal temporal quadrant in both groups (R = 0.589, p = 0.001 and R = 0.455, p = 0 .017, respectively). Our findings support that ranibizumab does not inhibit collateral vessel formation in eyes with superotemporal BRVO compared to dexamethasone implant. VD and vessel formation can positively affect the vision prognosis in long-term follow-up.

Suprarenal Inferior Vena Cava Ligation

Inferior vena cava (IVC) injuries account for about 25%–40% of abdominal vascular injuries. Blunt vena cava injury has a lower survival rate than penetrating injury. They may present with torrential bleed. In extreme cases, ligation of the IVC may have to be done as a damage control procedure. However, it is associated with significant morbidity and mortality, especially when the suprarenal IVC is ligated. It can lead to acute kidney injury and lower limb compartment syndrome. Suprarenal IVC ligation has been done in oncological resections, as it is a chronic disease that allows collateral vessel formation. However, there is a paucity of data on the ligation of the suprarenal IVC in acute trauma. We present a case of penetrating injury to the IVC which was managed initially by suprarenal IVC ligation, followed by synthetic interposition graft placement once the patient stabilized hemodynamically. The case highlights that this approach can be viable as a damage control procedure in exsanguinating patients.

Assessment of the embolization effect of temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) nanogels in the rabbit renal artery by CT perfusion and confirmed by macroscopic examination

Transcatheter embolization is an important treatment method in clinical therapy, and vascular embolization material plays a key role in embolization. The temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) (PIB) nanogel is a novel embolic agent. To evaluate the feasibility of the nanogel as a blood vessel embolization agent, we aimed to assess the effect of embolization with PIB nanogels in the rabbit renal artery by non-invasive computed tomography (CT) perfusion, macroscopic and histological examination. Ten healthy adult Japanese rabbits were used to implement RAE of PIB nanogels in their right kidneys. CT perfusion scans were performed pre- and post-treatment at various time-points (1, 4, 8, and 12 weeks). Two rabbits were euthanized and histologically examined at each time-point, and the remaining rabbits were euthanized at 12 weeks after embolization. The RAE efficacy of the nanogels was further confirmed by macroscopic and histological examination. The renal volume and renal blood flow (BF) of the right kidney were significantly decreased post-treatment compared with those pre-treatment (volume: pre, 9278 ± 1736 mm3; post 1 week, 5155 ± 979 mm3, P < 0.0001; post 4 weeks, 3952 ± 846 mm3, P < 0.0001; post 8 weeks, 3226 ± 556 mm3, P < 0.0001; post 12 weeks, 2064 ± 507 mm3, P < 0.0001. BF: pre, 530.81 ± 51.50 ml/min/100 ml; post 1 week, 0 ml/min/100 ml, P < 0.0001; post 4 weeks, 0 ml/min/100 ml, P < 0.0001; post 8 weeks, 0 ml/min/100 ml, P < 0.0001; post 12 weeks, 0 ml/min/100 ml, P < 0.0001). No revascularization or collateral circulation was observed on histological examination during this period, and PIB nanogels were dispersed in all levels of the renal arteries. Twelve weeks after embolization, CT perfusion showed no BF in the right renal artery and renal tissue, a finding that was consistent with histological examination showing complete embolization of the right renal artery with a lack of formation of collateral vessels. The effect of embolization on PIB was adequate, with good dispersion and permanency, and could be evaluated by non-invasive and quantitative CT perfusion.

Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb.

Aims:Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling.Methods:Nondiabetic and diabetic mice, with (ec-Prkcd−/−) or without (ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs.Results:Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd−/− mice. VEGF signaling pathway was restored in diabetic ec-Prkcd−/− mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity.Conclusions:Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.

Effects of High Fat Versus Normal Diet on Extracellular Vesicle-Induced Angiogenesis in a Swine Model of Chronic Myocardial Ischemia.

BackgroundMesenchymal stem cell–derived extracellular vesicles (EVs) promote angiogenesis in the ischemic myocardium. This study examines the difference in vascular density, myocardial perfusion, molecular signaling, and gene expression between normal diet (ND) and high fat diet (HFD) groups at baseline and following intramyocardial injection of EVs.Methods and ResultsIntact male Yorkshire swine fed either an ND (n=17) or HFD (n=14) underwent placement of an ameroid constrictor on the left circumflex coronary artery. Subsequently, animals received either intramyocardial injection of vehicle‐saline as controls; (ND‐controls n=7, HFD‐controls, n=6) or EVs; (ND‐EVs n=10, HFD‐EVs n=8) into the ischemic territory. Five weeks later, myocardial function, perfusion, vascular density, cell signaling, and gene expression were examined. EVs improved indices of myocardial contractile function, myocardial perfusion, and arteriogenesis in both dietary cohorts. Interestingly, quantification of alpha smooth muscle actin demonstrated higher basal arteriolar density in HFD swine compared with their ND counterparts; whereas EVs were associated with increased CD31‐labeled endothelial cell density only in the ND tissue, which approached significance. Levels of total endothelial nitric oxide synthase, FOXO1 (forkhead box protein O1) , transforming growth factor‐β, phosphorylated VEGFR2 (vascular endothelial growth factor receptor 2), and phosphorylated MAPK ERK1/ERK2 (mitogen‐activated protein kinase) were higher in ischemic myocardial lysates from ND‐controls compared with HFD‐controls. Conversely, HFD‐control tissue showed increased expression of phosphorylated endothelial nitric oxide synthase, phosphorylated FOXO1, VEGFR2, and MAPK ERK1/ERK2 with respect to ND‐controls. Preliminary gene expression studies indicate differential modulation of transcriptional activity by EVs between the 2 dietary cohorts.ConclusionsHFD produces a profound metabolic disorder that dysregulates the molecular mechanisms of collateral vessel formation in the ischemic myocardium, which may hinder the therapeutic angiogenic effects of EVs.

Changes in Brain Functional Network Connectivity in Adult Moyamoya Diseases.

The online version contains supplementary material available at (10.1007/s11571-021-09666-1).