Injured Arteries Research Articles

Post paracentesis deep circumflex iliac artery injury identified at angiography, an underreported complication

BackgroundThough injury to the inferior epigastric artery (IEA) is reported to be the most common source of hemorrhagic complications from paracentesis, we wish to present our experience involving deep circumflex iliac artery (DCIA) injuries that in our experience is the artery most frequently injured during paracentesis.MethodsSixteen patients with clinically significant hemorrhage following paracentesis were referred to our Interventional Radiology service for trans-catheter embolization. Patterns of hemorrhage from diagnostic cross-sectional imaging and subsequent angiographic findings and management were investigated.Results8/16 patients (50%) had angiographic evidence of injury to the DCIA and 4/16 patients (25%) had evidence of injury to the IEA, with two of these patients demonstrating hemorrhage from both the DCIA and IEA; 3/16 patients had injuries to subcostal and/or intercostal arteries; while 3/16 patients had negative angiograms. All patients underwent embolization of the identified injured arteries, and empiric embolization was performed of the DCIA and/or IEA in the three patients with negative angiograms. Fourteen of sixteen patients stabilized post embolization, while two patients required a second embolization procedure to achieve hemostasis; all patients were subsequently discharged home in stable condition.ConclusionBoth the IEA and the lesser known DCIA need to be considered when performing paracentesis and at subsequent angiography for post paracentesis iatrogenic hemorrhage. Knowledge of both of these at-risk abdominal wall arteries may help minimize hemorrhagic complications from paracentesis.

Vascular Injuries Due to Penetrating Missile Trauma in Anti-Terrorism Ops

Purpose: Penetrating vascular trauma though less common poses a challenge to all Surgeons. This study was designed to analyse the profile, management modalities of vascular trauma and the outcomes thereof at a Trauma Care Centre in a Tertiary care setting in hostile environment in India. Methods: A prospective review of all patients with arterial and venous injuries being transferred to the Trauma Center at out Tertiary Care Center between June 2015 and May 2018 was done. Demographics, admission data, treatment, and complications were reviewed. Results: There were a total of 46 patients with 65 vascular injuries, 39 arterial injuries and 26 venous injuries. The age range was 21 to 47 years. Nineteen patients had both arterial and venous injuries. A total of 42 cases presented within 12 hours of injury and complete arterial transections were found in 33 cases (80.49%). There were three mortalities (6.52%) and three amputations (8.33%). The overall limb salvage rate was 91.67% with popliteal artery being the commonest injured artery. Poor prognosticators for limb salvage were increasing time to present to the trauma centre, hypovolemic shock, multi-organ trauma and associated venous injuries. Conclusions: Penetrating missile trauma leading to vascular injuries has not been widely reported. Attempting limb salvage even in cases with delayed presentation should be weighed with the threat to life before revascularisation and should preferably be done at a centre with vascular expertise. A team approach with vascular, orthopaedic, general surgeons, and critical care anaesthesiologists all aboard improve the outcomes manifold. Use of tourniquets and early fasciotomies have been emphasized as is the use of native veins as the bypass conduit. This is probably the largest study on penetrating Vascular trauma in anti-terrorism ops from the Indian subcontinent. It highlights the significance of prompt recognition and availability of vascular expertise in optimally managing cases of vascular trauma.

Emergency Repair of Severe Limb Injuries With Free Flow-Through Chimeric Anterolateral Thigh Perforator Flap.

Complex limb trauma often involves both soft tissue and vascular defects, and is challenging for surgeons. The traditional musculocutaneous flap cannot achieve a 3-dimensional wound repair. Here we report our experience with a single-stage reconstruction and revascularization performed on complex extremity injuries using a free flow-through chimeric anterolateral thigh perforator (ALTP) flap. Seventeen patients (16 men; aged 19-55 years) with complex soft tissue defects attended our hospital from January 2010 to November 2017. All patients underwent reconstruction based on free flow-through chimeric ALTP flap for complex injuries in their extremities. The wound size ranged from 16 × 8 to 45 × 30 cm. The injured artery was flow-through anastomosed with the descending branch of the lateral femoral circumflex artery to regain blood flow. The muscle flap was used to fill the deep dead space on the injury site. The skin and fascial flaps were used for superficial cover. The donor site defects were sutured directly in 6 patients; simultaneous skin grafts were applied in the remaining 11 patients. The ALTP flaps survived in 15 patients. Failure necessitated limb amputation in 2 patients. Six patients received both skin and fasciae flaps; 11 received flaps comprising the skin, fasciae, and vastus lateralis muscle. Partial necrosis after skin grafting was observed in 11 patients, and the wounds healed either by dressing change (1 patient) or second skin graft (10 patients). All donor sites healed without complications. All patients were followed up for 5 to 60 months (mean, 21.8 months). The flow-through chimeric ALTP flap can be used for 1-stage reconstruction of 3-dimensional soft tissue defects and vascular gap. It is feasible for managing complex injuries of both the upper and lower extremities in emergency settings.

Strain‐selective efficacy of sacubitril/valsartan on carotid fibrosis in response to injury in two inbred mouse strains

Sacubitril/valsartan (Sac/val) is more effective than valsartan in lowering BP and mortality in patients with heart failure. Here, we proposed that Sac/val treatment would be more effective in preventing pathological vascular remodelling in 129X1/SvJ (129X1), than in C57BL/6J (B6) inbred mice. Sac/val (60mg·kg-1 ·day-1 ) and valsartan (27mg·kg-1 ·day-1 ) were given as prophylactic or therapeutic treatments, to 129X1 or B6 mice with carotid artery ligation for 14 days. Blood flow was measured by ultrasound. Ex vivo, carotid tissue was analysed with histological and morphometric techniques, together with RNA sequencing and gene ontology. Sac/val was more effective than valsartan in lowering BP in 129X1 compared with B6 mice. Liver expression of CYP2C9 and plasma cGMP levels were similar across treatments. A reduction in carotid thickening after prophylactic treatment with valsartan or Sac/val also resulted in significant arterial shrinkage in B6 mice. In 129X1 mice, Sac/val and prophylactic treatment with valsartan had no effect on carotid thickening but preserved carotid size. BP lowering significantly correlated with a decline in carotid stiffness (R2 =.37, P=.0096) in 129X1 but not in B6 mice. The gene expression signature associated with hyalurononglucosaminidase activity was down-regulated in injured arteries after both regimens of Sac/val only in 129X1 mice. Administration of Sac/val but not valsartan significantly reduced deposition of hyaluronic acid and carotid fibrosis in 129X1 mice. These results underscore the importance of the genetic background in the efficacy of the Sac/val on vascular fibrosis.

Transmembrane protein 66 attenuates neointimal hyperplasia after carotid artery injury by SOCE inactivation.

Neointimal hyperplasia could be one of the most important complications after balloon angioplasty. Since calcium signaling has several physiologic effects on the regulation of the proliferation and migration of vascular smooth muscle cells (VSMCs), it was hypothesized that transmembrane protein 66 (TMEM66), a store operated calcium entry (SOCE)‑associated regulatory factor, possesses vascular protection against balloon injury. The rat balloon‑induced carotid artery injury model was performed. Histological analysis was used to check neointimal hyperplasia. TMEM66 expression was measured by PCR and immunoblotting. The results revealed that TMEM66 was expressed in the medial and neointimal layers of the injured artery, and the expression of TMEM66 was markedly decreased. TMEM66 overexpression attenuated neointimal hyperplasia via VSMC proliferation/migration inhibition, and restored expression of VSMC phenotypic markers. Moreover, TMEM66 overexpression reduced the increased expression of Stim1 and Orai1 and PDGF‑BB treatment‑enhanced [Ca2+]i. In conclusion, TMEM66 protects against balloon injury‑induced neointimal hyperplasia, and may be a pharmacological target for the treatment of restenosis.

2079-P: Association of Serum FAM19A5 with Metabolic and Vascular Risk Factors in Human Subjects With or Without Type 2 Diabetes

Introduction: A recent in-vitro and in-vivo experimental study has revealed that family with sequence similarity 19 [chemokine (C-C motif)-like] member A5 (FAM19A5), a novel secreted adipokine has inhibitory effects on proliferation and migration of vascular smooth muscle cells, and neointima formation of injured arteries. However, the relationship between serum FAM19A5 level and cardio-metabolic risks has not been evaluated in humans. For the first time, we investigated the association between serum FAM19A5 concentration with various metabolic and vascular risk factors in human subjects with or without type 2 diabetes. Methods: Circulating FAM19A5 concentration was measured in 223 individuals (45 without diabetes and 178 with type 2 diabetes), and the association of FAM19A5 level with cardio-metabolic risk factors including body composition, plasma glucose, glycated hemoglobin (HbA1c), and atherosclerosis was explored. Results: Serum FAM19A5 (pg/ml) was higher in patients with type 2 diabetes [172.70 (116.19, 286.42)] compared with that in individuals without diabetes [92.09 (70.32, 147.24)] (p<0.001). Advance in serum FAM19A5 tertile was associated with a trend of increase in waist hip ratio (WHR), fasting plasma glucose (FPG), and mean brachial-ankle pulse wave velocity (baPWV) values. Serum FAM19A5 was positively correlated with waist circumference, WHR, alanine aminotransferase, FPG, HbA1c, and mean baPWV values. Multiple stepwise regression analysis identified WHR, low density lipoprotein cholesterol, and baPWV as determining factors for log-transformed serum FAM19A5 concentration (R2=0.0689). Discussion: A novel adipokine FAM19A5 was closely related to various metabolic and vascular risk factors in human subjects, suggesting its potential as a biomarker of cardio-metabolic disease in humans. Disclosure Y. Lee: None. J.A. Kim: None. E. Roh: None. S. Hong: None. K. Choi: None. S. Baik: None. H. Yoo: None.

Chronological Change of Vascular Reactivity to cGMP Generators in the Balloon-Injured Rat Carotid Artery

Background/Aims: Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators. Methods: Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points. In addition, sGC expression was detected by immunohistochemistry. Results: At 1 day after injury, acidified sodium nitrite-induced relaxation was attenuated in the injured artery, whereas BAY 60-2770-induced relaxation was augmented. Similar attenuation of response to acidified sodium nitrite was seen at 7 and 14 days after injury. On the other hand, the augmentation of response to BAY 60-2770 disappeared at 7 and 14 days after injury. At 1 day after injury, the immunohistochemical expression pattern of sGC in the smooth muscle layer of the injured artery was not different from that of the uninjured artery. However, in the injured artery, the intensity of sGC staining was weak at 7 and 14 days after injury. Conclusion: Balloon injury alters vascular responsiveness to cGMP generators, which seems to be associated with the form and/or expression of sGC.

Effects of conjugated estrogen and bazedoxifene on hemostasis and thrombosis in mice.

Estrogen–progestin therapy was previously considered as the standard of care for managing bothersome symptoms associated with menopause, but it increases risks of breast cancer and of thromboembolism. The combination of conjugated estrogen (CE) with bazedoxifene (BZA) named tissue-selective estrogen complex (TSEC) was designed to minimize or even abrogate the undesirable effects on breast, while maintaining the beneficial effects such as prevention of osteoporosis and suppression of climacteric symptoms. The risk on thromboembolism associated with TSEC is unknown, although the clinical available data are reassuring. The aim of this study was to define the impact of a chronic administration of CE, BZA or CE + BZA on hemostasis and thrombosis in ovariectomized mice. As expected, CE, but not BZA neither CE + BZA, induced uterine and vagina hypertrophy. As previously demonstrated for 17β-estradiol (E2), we found that CE (i) increased tail-bleeding time, (ii) prevented occlusive thrombus formation in injured carotid artery and (iii) protected against collagen/epinephrine-induced thromboembolism. Thus, whereas BZA antagonized CE action on reproductive tissues, it had no impact on the effect of CE on hemostasis, thromboembolism and arterial thrombosis in mice. CE + BZA shared the anti-thrombotic actions of CE in these mouse models. If a similar process is at work in women, CE combined with BZA could contribute to minimize the risk of thrombosis associated with hormone replacement therapy.

Role of epicardial adipose tissue NPR-C in acute coronary syndrome

Background and aimsIt has been suggested that epicardial adipose tissue (EAT) thermogenesis plays a role in coronary artery disease (CAD). Recent evidence indicates that natriuretic peptide receptors (NPRs) are critical for thermogenesis. We determined the expression and signaling of NPRs in EAT in the context of CAD progression and their association with brown fat-related genes, such as uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α). MethodsNPR-A, NPR-B and NPR-C mRNA and protein expression levels were analyzed in EAT and thoracic subcutaneous adipose tissue (SAT) from non-CAD (NCAD), stable CAD and acute coronary syndrome (ACS) patients. The associations of NPRs with thermogenic genes were also evaluated. ResultsThe EAT of ACS patients showed lower NPR-C gene and protein expression levels compared with that of stable CAD or NCAD patients. NPR-C mRNA expression in EAT also decreased as the number of injured arteries rose, and correlated positively with left ventricular ejection fraction and EAT PGC1α mRNA expression. EAT PGC1α and UCP1 gene expression levels also decreased in the ACS group. Linear and logistic regression models showed associations of EAT NPR-C mRNA levels with EAT PGC1α mRNA levels and the presence of ACS. Furthermore, the EAT of ACS patients showed reduced p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels, which correlated positively with NPR-C protein levels. ConclusionsThe EAT of patients with ACS is characterized by decreased NPR-C, reduced UCP1 and PGC1α mRNA expression levels and reduced activation of the p38 MAPK pathway. The associations among the expression of EAT NPR-C and ACS, and brown fat markers suggest that NPR-C may play a role in ACS and in the regulation of EAT brown-like fat features in humans.

Hydrogen sulfide improves vascular repair by promoting endothelial nitric oxide synthase-dependent mobilization of endothelial progenitor cells.

Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair after arterial injury. Hydrogen sulfide (H2S) is a novel gasotransmitter that regulates vascular homeostasis. We investigated whether exogenous H2S could facilitate EPCs in repairing arterial injury. Sodium hydrosulfide (NaHS), a precursor of H2S, promoted re-endothelialization and inhibited neointima formation in a rodent carotid artery injury model. Flow cytometric analysis revealed that NaHS treatment significantly increased the yield of EPCs after vascular injury. Furthermore, NaHS enhanced the capacity of EPCs to the luminal surface of injured arteries in wild-type mice, which had received a bone marrow transplantation from tie2-GFP donor mice. However, this enhancing effect was greatly attenuated in endothelial nitric oxide synthase knockout mice (eNOS). In-vitro incubation of human EPCs with NaHS not only increased the yield of EPCs, but also enhanced their adhesion and colony formation capacities. Treatment with an eNOS inhibitor (L-NAME) blocked the effects of NaHS on EPCs functions. H2S enhances eNOS-dependent mobilization of bone marrow-derived EPCs and facilitates re-endothelialization following vascular injury.

Oligonucleotide Microarrays Identified Potential Regulatory Genes Related to Early Outward Arterial Remodeling Induced by Tissue Plasminogen Activator.

Constrictive vascular remodeling limiting blood flow, as well as compensatory outward remodeling, has been observed in many cardiovascular diseases; however, the underlying mechanisms regulating the remodeling response of the vessels remain unclear. Plasminogen activators (PA) are involved in many of the processes of vascular remodeling. We have shown previously that increased levels of tissue-type PA (tPA) contributes to outward vascular remodeling. To elucidate the mechanisms involved in the induction of outward remodeling we characterized changes in the expression profiles of 8799 genes in injured rat carotid arteries 1 and 4 days after recombinant tPA treatment compared to vehicle. Periadventitial tPA significantly increased lumen size and vessel area, encompassed by the external elastic lamina, at both one and 4 days after treatment. Among 41 differentially expressed known genes 1 day after tPA application, five genes were involved in gene transcription, five genes were related to the regulation of vascular tone [for example, thromboxane A2 receptor (D32080) or non-selective-type endothelin receptor (S65355)], and eight genes were identified as participating in vascular innervation [for example, calpain (D14478) or neural cell adhesion molecule L1 (X59149)]. Four days after injury in tPA-treated arteries, four genes, regulating vascular tone, were differentially expressed. Thus, tPA promotes outward arterial remodeling after injury, at least in part, by regulating expression of genes in the vessel wall related to function of the nervous system and vascular tone.

Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice.

Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin-1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2-transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease.

The myristoylated alanine-rich C kinase substrate differentially regulates kinase interacting with stathmin in vascular smooth muscle and endothelial cells and potentiates intimal hyperplasia formation

ObjectiveRestenosis limits the durability of all cardiovascular reconstructions. Vascular smooth muscle cell (VSMC) proliferation drives this process, but an intact, functional endothelium is necessary for vessel patency. Current strategies to prevent restenosis employ antiproliferative agents that affect both VSMCs and endothelial cells (ECs). Knockdown of the myristoylated alanine-rich C kinase substrate (MARCKS) arrests VSMC proliferation and paradoxically potentiates EC proliferation. MARCKS knockdown decreases expression of the kinase interacting with stathmin (KIS), increasing p27kip1 expression, arresting VSMC proliferation. Here, we seek to determine how MARCKS influences KIS protein expression in these two cell types. MethodsPrimary human coronary artery VSMCs and ECs were used for in vitro experiments. MARCKS was depleted by transfection with small interfering RNA. Messenger RNA was quantitated with the real-time reverse transcription polymerase chain reaction. Protein expression was determined by Western blot analysis. Ubiquitination was determined with immunoprecipitation. MARCKS and KIS binding was assessed with co-immunoprecipitation. Intimal hyperplasia was induced in CL57/B6 mice with a femoral artery wire injury. MARCKS was knocked down in vivo by application of 10 μM of small interfering RNA targeting MARCKS suspended in 30% Pluronic F-127 gel. Intimal hyperplasia formation was assessed by measurement of the intimal thickness on cross sections of the injured artery. Re-endothelialization was determined by quantitating the binding of Evans blue dye to the injured artery. ResultsMARCKS knockdown did not affect KIS messenger RNA expression in either cell type. In the presence of cycloheximide, MARCKS knockdown in VSMCs decreased KIS protein stability but had no effect in ECs. The effect of MARCKS knockdown on KIS stability was abrogated by the 26s proteasome inhibitor MG-132. MARCKS binds to KIS in VSMCs but not in ECs. MARCKS knockdown significantly increased the level of ubiquitinated KIS in VSMCs but not in ECs. MARCKS knockdown in vivo resulted in decreased KIS expression. Furthermore, MARCKS knockdown in vivo resulted in decreased 5-ethynyl-2′-deoxyuridine integration and significantly reduced intimal thickening. MARCKS knockdown enhanced endothelial barrier function recovery 4 days after injury. ConclusionsMARCKS differentially regulates the KIS protein stability in VSMCs and ECs. The difference in stability is due to differential ubiquitination of KIS in these two cell types. The differential interaction of MARCKS and KIS provides a possible explanation for the observed difference in ubiquitination. The effect of MARCKS knockdown on KIS expression persists in vivo, potentiates recovery of the endothelium, and abrogates intimal hyperplasia formation.

Successful Surgery of Right Common Iliac Artery Injury during Lumbar Discectomy with Endovascular Balloon Occlusion of the Aorta Performed by Cardiologists.

A 19-year-old woman developed hypotension and abdominal distension during lumbar discectomy. Computed tomography revealed a right common artery injury and a large retroperitoneal hematoma. She was transferred to our hospital and brought to an angiography room directly. Endovascular balloon occlusion of the aorta was performed by cardiologists while surgeons were preparing for surgery. With the hemodynamics stabilized, the injured artery was repaired. In such a case, closing the artery as soon as possible, whether by clamping or by balloon occlusion, is vital. The ability to respond with a “Heart Team” is essential for a small-manpower hospital to rescue a patient with a serious condition.

Adipolin/CTRP12 protects against pathological vascular remodelling through suppression of smooth muscle cell growth and macrophage inflammatory response.

Secreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling. Adipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-β (TGF-β) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-β receptor II (TGF-βRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-βRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-β1 concentration in media from cultured VSMCs and macrophages. These data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

Long non-coding RNA-SRA promotes neointimal hyperplasia and vascular smooth muscle cells proliferation via MEK-ERK-CREB pathway

Long noncoding RNA-steroid receptor RNA activator (LncRNA-SRA) is transcribed from a class of noncoding genes, and plays a critical role in regulating cell proliferation. However, the effect of lncRNA-SRA remains unclear in vascular proliferative diseases. In the present study, we overexpressed lncRNA-SRA in vitro, then investigated the biological consequences. A vascular damage mice model was constructed by performing femoral artery wire injury. LncRNA-SRA was overexpressed in the injured arteries, and significantly promoted the expression of ki67, thereby caused an overall increase in neointima formation. LncRNA-SRA overexpression led to the proliferation and migration of vascular smooth muscle cells (VSMCs). By stimulating the phosphorylation of MEK, ERK and CREB (cyclic nucleotide responsive element binding protein), lncRNA-SRA promoted VSMC proliferation. Meanwhile, these effects were blocked by the MEK inhibitor U0126. Therefore, lncRNA-SRA promoted VSMC proliferation by activating the MEK-ERK-CREB pathway. LncRNA-SRA could be a promising therapeutic target in vascular diseases characterized by neointimal hyperplasia.

Vildagliptin Reduces Stenosis of Injured Carotid Artery in Diabetic Mouse Through Inhibiting Vascular Smooth Muscle Cell Proliferation via ER Stress/NF-κB Pathway.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel anti-hyperglycemic drugs for type 2 diabetes. It has been reported that DDP-4 inhibitor could exert pleiotropic effects on cardiovascular system. This study was to explore the effect and mechanism of vildagliptin on the stenosis of injured carotid artery in diabetic mouse. Twenty six-week-old male db/db mice (BKS) were randomized into vildagliptin treated and vehicle control groups. Ligation injury was first performed in left carotid arteries of all diabetic mice, then oral vildagliptin or equal amount of PBS was correspondingly administered to the mice from the next day to ligation injury for 4 weeks. Effects on proliferation were detected via histological and morphometric analysis. Endoplasmic reticulum (ER) stress and nuclear factor kappa B (NF-κB) markers were determined by immunoblot analysis. After 4 weeks of vildagliptin delivery, it was observed that the intimal area and neointimal thickness of the ligated carotid arteries were significantly reduced as compared to the control group. In vivo, vildagliptin suppressed the expressions of PCNA and α-SMA, phospho-p65, phospho-IKKα/β, GRP78 and CHOP, as well as IRE-1 in vascular smooth muscle cells (VSMCs). In vitro, the proliferation and hypertrophy of VSMCs were significantly inhibited by blocking the IRE-1 pathway, and the inhibition of phospho-IRE-1 expression down-regulated the expression of phospho-IKKα/β in VSMCs. Vildagliptin reduced the stenosis of injured carotid arteries in diabetic mice, and this effect was achieved via inhibiting the activation of ER stress/NF-κB pathway.

Mass Spectrometric Imaging Reveals Temporal and Spatial Dynamics of Bioactive Lipids in Arteries Undergoing Restenosis.

Restenosis, or renarrowing of the arterial lumen, is a common recurrent disease following balloon angioplasty and stenting treatments for cardiovascular disease. A major technical barrier for deciphering restenotic mechanisms is the dynamic, spatial profiling of bioactive lipids in the arterial wall, especially in small animals. Here, applying matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), we conducted the first lipidomic study of temporal-spatial profiling in a small animal model of angioplasty-induced restenosis. Cross sections were collected 3, 7, and 14 days after balloon angioplasty of rat carotid arteries. MALDI-MSI analyses showed that diacylglycerols (DAGs), signaling lipids associated with restenosis, and lysophosphatidylcholines (LysoPCs), whose function was uncharacterized in restenosis, dramatically increased at postangioplasty day 7 and day 14 in the neointimal layer of balloon-injured arteries compared to uninjured controls. In contrast, sphingomyelins (SMs) did not increase, but rather decreased at day 3, day 7, and day 14 in injured arteries versus the uninjured control arteries. These results revealed previously unexplored distinct temporal-spatial lipid dynamics in the restenotic arterial wall. Additionally, we employed time-of-flight secondary ion mass spectrometry (TOF-SIMS) tandem MS imaging for both molecular identification and imaging at high spatial resolution. These imaging modalities provide powerful tools for unraveling novel mechanisms of restenosis involving lipids or small signaling molecules.

LncRNA CRNDE regulates the proliferation and migration of vascular smooth muscle cells.

Restenosis after angioplasty or stent is a major clinical problem. While long noncoding RNAs (lncRNAs) are implicated in a variety of diseases, their role in restenosis is not well understood. This study aims to investigate how dysregulated lncRNAs and messenger RNAs (mRNAs) contribute to restenosis. By microarray analysis, we identified 202 lncRNAs and 625 mRNAs (fold change > 2.0, p < 0.05) differentially expressed between the balloon-injured carotid artery and uninjured carotid artery in the rats. Among differentially expressed lncRNAs, LncRNA CRNDE had the highest fold change and the change was validated by reverse transcription polymerase chain reaction. We found that LncRNA CRNDE was significantly upregulated in injured rat carotid artery and vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor-BB (PDGF-BB). Knockdown of LncRNA CRNDE by small interference RNA significantly inhibited PDGF-BB stimulated proliferation and migration of VSMCs. Moreover, knockdown of LncRNA CRNDE attenuated PDGF-BB-induced phenotypic change of VSMCs. Taken together, our study reveals a novel mechanoresponsive LncRNA CRNDE which may be a therapeutic target for restenosis.

Abstract WP533: Chronic Cerebral Damage Aggravates Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model

Introduction: Distant organ dysfunction has been highlighted whereby acute or chronic damage in one organ may induce dysfunctions of the other organs such as cardiorenal syndrome. Vascular injury is an important process in various vascular diseases. However, the relationship cerebral ischemic damage and peripheral vascular disorder is still unclear. Therefore, we have investigated the possible pathophysiological interactions between brain ischemia and vascular remodeling. Methods: Eight-week-old male C57BL/6 mice underwent permanent cerebral brain ischemia by permanent occlusion of the left middle cerebral artery occlusion (MCAO) by electrocoagulation using a subtemporal approach. Four weeks after MCAO, vascular injury was induced by polyethylene cuff placement on the femoral artery. Neointima formation was determined 14 days after cuff placement by evaluating intima/media ratio. Mice were administrated 0.5% tempol, antioxidant agent, in drinking water from after MCAO. Macrophage fractions in spleen two weeks after MCAO were examined and M1 and M2-polarized macrophages were separated by flow cytometry and analyzed. Results: Cerebral ischemia did not influence the intima/media ratio 6 weeks after MCAO compared with sham-operated mice. Neointima formation in the injured artery was significantly increased 2 weeks after cuff placement. Interestingly, the neointima formation 2 weeks after cuff placement was more marked in MCAO-operated mice compared with sham-operated mice. We observed that treatment with tempol did not improve increased neointima formation in MCAO-operated mice. Next, we examined the macrophage fractions in spleen 2 weeks after MCAO. The macrophage fraction in SVF evaluated by F4/80 staining did not differ between sham- and MCAO-operated mice. There was no significant difference in M1 and M2 fraction with/without MCAO. Conclusion: These results suggest that cerebral ischemic injury aggravate peripheral vascular disorders, and we are addressing the possible roles of renin-angiotensin system and inflammation etc. involved in these interesting results, which could provide us with the discovery of new pathological mechanisms concerning the distant organ dysfunctions between brain and peripheral vasculature.