Femoral Artery Injury Research Articles

Prevention and treatment of vascular complications of inguinal hernia repair

Objective To explore the prevention and treatment of complications of vascular injury after inguinal hernia repair. Methods The retrospective cross-sectional and descriptive study was adopted. The clinical data of 22 patients with vascular injury after inguinal hernia repair who were admitted to the First Affiliated Hospital of Chongqing Medical University between June 2005 and March 2016 were collected. Observation indicators included: (1) the vascular complications after inguinal hernia repair: vascular injury, peritoneal interstitial hemorrhage or hematoma formation, thrombosis and vascular embolization, (2) treatment, (3) follow-up. Patients were followed up by telephone interview at 15 days after discharge up to April 2016, and conditions of patients, recovery of symptoms and subsequent pharmacotherapy were detected. Results (1) The vascular complications after inguinal hernia repair: of 22 patients, peritoneal interstitial hemorrhage or hematoma formation was detected in 8 patients (vascular injury of corona mortis in 2 patients, inferior epigastric artery injury in 3 patients and unexplained peritoneal interstitial hemorrhage in 3 patients), femoral vein injury in 3 patients, femoral artery injury in 1 patient, deep vein thrombosis of the double lower limbs in 8 patients (including 2 with pulmonary embolism) and femoral and popliteal artery embolism in 2 patients. (2) Treatments: 20 of 22 patients had good therapeutic effect, 1 patient with arterial embolism received timely treatment avoiding the necrosis of limbs, 1 ischemic necrosis of partial toes and the other patients had good effect through vascular repair or construction. One patient with inferior epigastric artery injury and 1 with femoral vein injury died of hemorrhagic shock. (3) Follow-up: 20 of 22 patients were followed up for 2 weeks, with good conditions. Patients′ hemorrhage had been improved. The symptoms of patients with deep vein thrombosis and arterial embolism of lower limbs didn′t become obviously aggravated, and they took the medicine as medical advice. Conclusion The different treatments are conducted according to the occuring characteristics of vascular complications, with better outcomes. Key words: Inguinal hernia; Hernia repair; Iatrogenic injury; Vascular injury; Therapy

Distinct Differences on Neointima Formation in Immunodeficient and Humanized Mice after Carotid or Femoral Arterial Injury.

Percutaneous coronary intervention is widely adopted to treat patients with coronary artery disease. However, restenosis remains an unsolved clinical problem after vascular interventions. The role of the systemic and local immune response in the development of restenosis is not fully understood. Hence, the aim of the current study was to investigate the role of the human immune system on subsequent neointima formation elicited by vascular injury in a humanized mouse model. Immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl(NSG) mice were reconstituted with human (h)PBMCs immediately after both carotid wire and femoral cuff injury were induced in order to identify how differences in the severity of injury influenced endothelial regeneration, neointima formation, and homing of human inflammatory and progenitor cells. In contrast to non-reconstituted mice, hPBMC reconstitution reduced neointima formation after femoral cuff injury whereas hPBMCs promoted neointima formation after carotid wire injury 4 weeks after induction of injury. Neointimal endothelium and smooth muscle cells in the injured arteries were of mouse origin. Our results indicate that the immune system may differentially respond to arterial injury depending on the severity of injury, which may also be influenced by the intrinsic properties of the arteries themselves, resulting in either minimal or aggravated neointima formation.

Contemporary outcomes of civilian lower extremity arterial trauma

Lower extremity arterial injury may result in limb loss after blunt or penetrating trauma. This study examined outcomes of civilian lower extremity arterial trauma and predictors of delayed amputation. The records of patients presenting to a major level I trauma center from 2004 to 2014 with infrainguinal arterial injury were identified from a prospective institutional trauma registry, and outcomes were reviewed. Standard statistical methods were used for data analysis. We identified 149 patients (86% male; mean age, 33± 14years,). Of these, 46% presented with blunt trauma: 19 (13%) had common femoral artery, 26 (17%) superficial femoral artery, 50 (33%) popliteal, and 54 (36%) tibial injury. Seven patients underwent primary amputation; of the remainder, 21 (15%) underwent ligation, 85 (59%) revascularization (80% bypass grafting, 20% primary repair), and the rest were observed. Delayed amputation was eventually required in 24 patients (17%): 20 (83%) were due to irreversible ischemia or extensive musculoskeletal damage, despite having adequate perfusion. Delayed amputation rates were 26% for popliteal, 20% for tibial, and 4.4% for common/superficial femoral artery injury. The delayed amputation group had significantly more (P< .05) blunt trauma (79% vs 30%), popliteal injury (46% vs 27%), compound fracture/dislocation (75% vs 33%), bypass graft (63% vs 43%), and fasciotomy (75% vs 43%), and a higher mangled extremity severity score (6.1± 1.8 vs 4.3± 1.6). Predictors of delayed amputation included younger age, higher injury severity score, popliteal or multiple tibial injury, blunt trauma, and pulseless examination on presentation. Individualized decision making based on age, mechanism, pulseless presentation, extent of musculoskeletal trauma, and location of injury should guide the intensity of revascularization strategies after extremity arterial trauma. Although patients presenting with vascular trauma in the setting of multiple negative prognostic factors should not be denied revascularization, expectations for limb salvage in the short-term and long-term periods should be carefully outlined.

Safety of the long-term application of QuikClot Combat Gauze, ChitoGauze PRO and Celox Gauze in a femoral artery injury model in swine - a preliminary study.

The purpose of this study was to examine the safety of the long-term application of QuikClot Combat Gauze, ChitoGauze PRO and Celox Gauze using a swine model. The study was conducted on nine pigs weighing approximately 30 kg, which were randomly divided into three groups. Under deep anesthesia, the pigs underwent complete transverse cutting of the femoral artery in the groin region. Hemostatic dressings were left in the wound for 24 hours. The animals were euthanized 24 hours after dressing application. In each group, macroscopic and microscopic severe changes and shock symptoms were observed in the lungs, liver, kidneys and heart. Fibrino-gaseous embolic material was found in the pulmonary artery of each group and in the lung vessels of the animals from the ChitoGauze PRO and Celox Gauze groups. In conclusion, the long-term application of the evaluated hemostatic dressings has the risk of coagulopathy and reaching the progressive stage of shock. The residues from the hemostatic dressings can ingress into the systemic circulation, thereby increasing the risk of embolus formation. Because of these harmful effects, the evaluated hemostatic dressings are not appropriate for long-term use. Future studies are needed on the consequences of the long-term application of these hemostatic agents.

Abstract 176: O-GlcNAc Transferase Promotes Vascular Smooth Muscle Cell De-differentiation

Vascular smooth muscle cells (VSMCs) in mature vessels have a differentiated, contractile phenotype but retain the ability to reversibly de-differentiate in response to environmental cues. Plasticity is necessary for development and wound healing, but also contributes to pathologies such as atherosclerosis and intimal hyperplasia. O- linked N- acetylglucosamine ( O -GlcNAc) transferase (OGT) mediates nutrient-sensitive post-translational modification of serine and threonine residues and has been implicated in multiple diseases, but its role in VSMC phenotypic modulation is not known. In human coronary SMCs, we found that OGT knockdown significantly increased contractile marker expression, including MYH11 and ACTA2, at the mRNA and protein levels. OGT knockdown also decreased proliferation rates after serum treatment in VSMCs. In addition, rapamycin, a differentiating agent, decreased OGT protein expression and O- GlcNAc levels. Conversely, de-differentiation with PDGF treatment increased OGT expression and global O- GlcNAc. Neither treatment affected OGT mRNA levels. OGT has been shown to increase the protein stability of EZH2, the enzyme that generates the inhibitory histone epigenetic mark H3K27me3. We found that OGT knockdown did not affect EZH2 mRNA levels but significantly decreased EZH2 protein expression as well as global H3K27me3 in VSMCs. Similar to OGT, EZH2 expression was decreased upon rapamycin treatment and increased with PDGF. A decrease in ubiquitination of EZH2 was observed after PDGF treatment, suggesting an increase in protein stability. Importantly, EZH2 knockdown increased protein expression of SMC contractile markers while EZH2 overexpression repressed these markers. Wire injury of mouse femoral arteries increased H3K27me3 levels after 21 days. OGT expression was elevated in the innermost layer of the neointima at the same time point. These data demonstrate that OGT inhibits VSMC differentiation and that OGT and its target EZH2 are both dynamically regulated during phenotypic modulation. Future work will illuminate if OGT promotes VSMC de-differentiation through EZH2-mediated histone modification at contractile gene promoters.

Randomized controlled trial comparing dynamic simulation with static simulation in trauma.

Current general surgery residents have limited exposure to open trauma operative cases. Simulation supplements variable rotation volume and provides experience with critical but rarely performed procedures. Open simulation classically focuses on static models with anatomic accuracy but lacks practicality when hemorrhage control is the lifesaving maneuver. We sought to evaluate whether training on a dynamic simulator, while much less expensive than training on a static cadaver, might be at least as effective in training surgery residents to expeditiously place temporary vascular shunts (TVSs). Our research team developed an inexpensive, reusable dynamic simulator with ongoing hemorrhage to instruct trainees in the steps of TVS placement. We enrolled 54 general surgery residents in a noninferiority randomized controlled trial comparing training of TVS placement on the dynamic simulator (n = 28) versus a cadaver arm (n = 26). After standardized video didactics, trainees practiced on either the simulator or cadaver arm. After the trainees achieved competency, they were tested on placing a TVS for a live swine femoral artery injury. Two blinded trauma surgeons evaluated the recorded performances. Residents did not differ in baseline characteristics between groups, and all residents in both groups successfully completed the TVS placement test. Subjects trained on the simulator placed the TVS faster than those trained on a cadaver (584 seconds vs. 751 seconds; difference, +167 seconds faster; 90% confidence interval [CI], +52 to +282 seconds), with a trend toward faster time to hemorrhage control (110 seconds vs. 148 seconds; difference, +38 seconds faster; 90% CI, -8 to +84). There was no significant difference in Objective Structured Assessment of Technical Skills scores (3.72 vs. 3.44; difference, +0.27 units better; 90% CI, -0.04 to +0.59). Training on a dynamic simulator resulted in noninferior time to completion of vascular shunt placement compared with training on a cadaver. The addition of dynamic hemorrhage to simulators might inexpensively augment trauma skills training.

Abstract 186: Hdac7-derived 7aa Peptide May Function as a Phosphorylation Carrier

Background: Histone deacetylase 7 (HDAC7) belongs to class II HDAC family, playing a pivotal role in the maintenance of endothelium integrity. There are 8 splicing variants in mouse HDAC7 mRNAs. Within the 5’ terminal non-coding area of some variants, there exist some short open reading frames (sORFs). Whether these sORFs can be translated and their potential roles in cellular physiology remain unclear. Method and results: Our previous studies suggested that one mouse HDAC7 produced a 7aa peptide from the non-coding area. In this study, we demonstrated that one sORF encoding a 7 amino acids (aa)-peptide could be translated in response to vascular endothelial cell growth factor (VEGF) in vascular progenitor cells (VPCs). The 7aa-peptide (7A) could be phosphorylated at serine residue via MEKK1. Importantly, the phosphorylated 7aa-peptide (7Ap) could transfer the phosphorylation group to the Thr residue of the 14-3-3γ protein in a cell free in-gel buffer system. The in vitro functional analyses revealed that 7A enhanced VEGF-induced VPC migration and differentiation toward endothelial cell (EC) lineage, in which MEKK1 and 14-3-3γ served as upstream kinase and downstream effector respectively. Knockdown of either MEKK1 or 14-3-3γ attenuated VEGF-induced VPC migration and differentiation. Exogenous 7Ap could rescue VEGF effect in MEKK1 but not in 14-3-3γ knockdown cells. The in vivo studies showed that 7A especially 7Ap induced capillary vessel formation within matrigel plug assays, increased re-endothelialization and suppressed neointima formation in the femoral artery injury model, and promoted the foot blood perfusion recovery in the hindlimb ischemia model. Conclusion: These results indicate that the sORFs within the non-coding area can be translated under some circumstances and that the 7aa-peptide may play an important role in cellular processes like migration and differentiation via acting as a phosphorylation carrier. Significance: As a phosphorylation carrier, 7aa possesses therapeutic potentials in tackling angiogenesis related diseases.

Active nano/microbilayer hemostatic agents for diabetic rat bleeding model.

Patients with diabetes mellitus have an increased cardiovascular risk due to the abnormality of hemostatic system components. Therefore, hemostasis is an important concept when considering that diabetics are under risk due to potential bleeding complications during surgical operation. The aim of our study was to examine the efficiency of a fabricated nano/microbilayer hemostatic dressing for bleeding control in diabetic patients. For this purpose, we prepared a nano/microbilayer hemostatic dressing that has a porous sublayer, including chitosan (CTS), bacterial cellulose (BC) as basement and active agents in coagulation cascade, such as vitamin K (Vit K), protamine sulfate (PS), and kaolin (Kao) as a filler and an upper layer consisting of silk fibroin (SF) or SF/phosphatidylcholine (PC) blend to achieve complete hemostasis in diabetic rats. Coagulative performances of the prepared hemostatic dressings were examined by the determination of bleeding time, blood loss, and mortality rate through diabetic rat femoral artery injury model. The percent of diabetic rat blood absorption was found to be 247±5% for gauze as opposed to 2214±56% for SF-coated PS/BC/CTS. Vit K-reinforced within 138s and SF-coated BC/CTS hemostatic dressings within 144s showed a rapid coagulation time. In vivo coagulation studies demonstrated that hemostatic agent-reinforced BC/CTS hemostatic dressing, especially PS/BC/CTS showed a significant hemostatic plug formation. This study suggests that the high positive charge and porosity give to these hemostatic agents reinforced hemostatic dressings the ability to rapidly swell and to promote the accumulation of red blood cells and platelets through electrostatic interactions. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1573-1585, 2017.

Percutaneous Common Carotid Artery Access for Pediatric Interventional Cardiac Catheterization.

Surgical cutdown for access to the common carotid artery provides a more direct route for certain pediatric cardiac interventions and avoids femoral artery injury in small infants. The safety of percutaneous carotid access (PCA) in children is unknown. Retrospective review of PCA at Texas Children's Hospital and Children's Healthcare of Atlanta. From July 2006 to November 2014, 42 patients underwent 47 attempts at catheterization via PCA. Median (range) age was 20 days (0 days-2.9 years) and weight was 3.2 kg (1.1-12.2). Two patients had failed PCA with no sequelae. Of the 45 catheterizations with successful PCA and sheath placement, 44 interventions were performed, the most common being stenting or stent redilation of the ductus arteriosus, balloon aortic valvuloplasty, and stenting or angioplasty of Blalock-Taussig shunts. After sheath withdrawal, hemostasis was achieved with manual compression, with no need for surgical control of bleeding. Follow-up carotid imaging was performed in all. Acutely, 3 patients developed carotid thrombosis with resolution in 1 and mild residual narrowing in 2 after anticoagulation therapy. At follow-up, 40 of 42 patients (95%) had a normal carotid artery, with 2 instances of mild stenosis. There were no neurological sequelae attributable to PCA. PCA is safe even in small infants, and hemostasis can be achieved without surgical repair, with a carotid patency rate superior to published data after surgical cutdown. Surgical cutdown is not routinely required for pediatric cardiac catheterization via the carotid artery.

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways.

Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-β and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.

PolySTAT-modified chitosan gauzes for improved hemostasis in external hemorrhage

Positively-charged chitosan gauzes stop bleeding from wounds by electrostatically interacting with negatively-charged cell membranes of erythrocytes to cause erythrocyte agglutination and by sealing wounds through tissue adhesion. In the following work, nonwoven chitosan gauze was impregnated with PolySTAT, a synthetic polymer that enhances coagulation by cross-linking fibrin, to generate PolySTAT/chitosan gauzes with improved hemostatic efficacy. When comparing nonwoven chitosan and PolySTAT/chitosan to a commercially-available chitosan-containing gauze (Celox® Rapid), no appreciable differences were observed in fiber size, morphology, and pore size. However, PolySTAT/chitosan demonstrated more rapid blood absorption compared to Celox® Rapid. In a rat model of femoral artery injury, PolySTAT/chitosan gauzes reduced blood loss and improved survival rate compared to non-hemostatic controls and Celox® Rapid. While Celox® Rapid had stronger adherence to tissues compared to PolySTAT/chitosan gauzes, blood loss was greater due to hematoma formation under the Celox® dressing. Animals treated with PolySTAT/chitosan gauzes required less saline infusion to restore and maintain blood pressure above the target blood pressure (60mmHg) while other treatment groups required more saline due to continued bleeding from the wound. These results suggest that PolySTAT/chitosan gauzes are able to improve blood clotting and withstand increasing arterial pressure with the addition of a fibrin cross-linking hemostatic mechanism. Statement of significanceBlood loss remains one of the leading causes of death after traumatic injury in civilian populations and on the battlefield. Advanced biomaterials that interact with blood components and/or accelerate the clotting process to form a hemostatic plug are necessary to staunch bleeding after injury. Chitosan-based gauzes, which stop bleeding by causing red blood cell aggregation, are currently used on the battlefield and have shown variable performance under high pressure arterial blood flow in animal studies, suggesting that red blood cell aggregates require further mechanical stabilization for more reliable performance. In this work, we investigate the binding and cross-linking of fibrin, a major component in blood clots, on chitosan gauze fiber surfaces to structurally reinforce red blood cell aggregates.

Abstract 13492: Increasing Endothelial Insulin Sensitivity Rescues Vascular Function and Repair in Systemic Insulin Resistance by Restoring Nitric Oxide Bioavailability and Improving Endothelial Cell Migration

Introduction: Insulin resistance is independently associated with vascular disease. Insulin receptor haploinsufficient (IRKO) mice are hypertensive and exhibit endothelial dysfunction and impaired vascular repair despite normal glucoregulation. We hypothesise that endothelial insulin signalling is crucial for vascular function and that selectively restoring endothelial cell (EC) insulin signalling may rescue these vascular derangements. Methods: Transgenic mice with Tie-2-driven human IR expression in the endothelium (HIRECO) were bred with IRKO, providing HIRECOxIRKO (HxI) offspring. Metabolic assessment included glucose and insulin tolerance tests, ELISA for plasma insulin concentration and non-invasive blood pressure measurement. Femoral artery injury was performed with angioplasty wires; repair was quantified in Evans Blue-perfused vessels at day 4. Circulating endothelial progenitor cells (EPC) were counted using FACS and cultured from blood. Explanted aortic rings were exposed to phenylephrine (PE) before and after incubation with the NOS inhibitor L-NMMA in organ baths to assess vasomotor function. Boyden chamber assays were used to assess migration of cultured lung ECs to VEGF. Data are expressed as mean(SE) and compared using t-tests;*=p&lt;0.05. Results: HxI and IRKO had similar glucocompetence and basal insulin [0.8(0.1)ng/mL vs 0.7(0.2);p=0.8]. Systolic BP was lower in HxI [97(2)mmHg vs 106(3)*]. Vascular repair was improved in HxI [57(4)% vs 46(2)%*]. There was no recovery in EPC numbers by FACS [99(10) vs 105(15);p=0.74], nor in culture [0.4(0.1)/HPF vs 0.4(0.2);p=0.99]. HxI aortic rings showed less PE-induced constriction than IRKO [EC50 8.9(0.8)x10 7 nM vs 6.3(0.9)x10 7 *], with greater NO bioavailability [Post-L-NMMA PE EC50 4.1(0.8)x10 7 nM vs IRKO 6.1(1.8)x10 7 *]. ECs from HxI showed greater net migration to VEGF [6.3(1.3) vs 1.9(1.2)*]. Conclusion: HIRECOxIRKO show rescue of vascular function despite global insulin resistance. This is not associated with improved glucoregulation or EPC abundance; rather, it may relate to increased NO availability and enhanced EC migration. Our data support endothelial insulin sensitisation as a potential therapeutic target for vascular dysfunction in insulin resistance.

Synthesis and characterization of fast-swelling porous superabsorbent hydrogel based on starch as a hemostatic agent

The body can’t control massive bleeding without treatment. Different hemostatic agents have been prepared recently, but most of them are ineffective in severe bleeding and expensive or cause safety concerns. In this study, in order to achieve fast control of bleeding, we synthesized and characterized fast-swelling porous superabsorbent hydrogel (FSPSH) and investigated its use as a hemostatic agent. The FSPSH was prepared by grafting acrylic acid and acrylamide onto starch through free-radical polymerization in aqueous solution. The FSPSH was characterized by Fourier transform infrared, X-ray diffraction, field emission scanning electron microscope, and thermogravimetric analysis. Then, temporal swelling behavior and coagulation time experiments were used to predict the in vivo behavior of the FSPSH. The hemocompatibility of synthesized FSPSH was evaluated by hemolysis test and blood cells function. In vivo study using femoral artery injury in rat demonstrated the FSPSH’s ability to aid in rapid hemostasis. Furthermore, monitoring the rat on first and seventh day after femoral artery injury also showed no harmful effect. This study indicates that FSPSH adsorbs fluid and swells, thus forms a physical barrier to blood loss. FSPSH, moreover, as hemostat is simple to use, lightweight, stable, and harmless.

The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells.

17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor α (ERα) via 2 activation functions, AF1 and AF2, and can also activate membrane ERα. The role of E2 on the endothelium relies on membrane ERα activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMCs) are not fully understood. The aim of this study was to determine which cellular target and which ERα subfunction are involved in the preventive action of E2 on neointimal hyperplasia. To trigger neointimal hyperplasia of VSMC, we used a mouse model of femoral arterial injury. Cre-Lox models were used to distinguish between the endothelial- and the VSMC-specific actions of E2. The molecular mechanisms underlying the role of E2 were further characterized using both selective ERα agonists and transgenic mice in which the ERαAF1 function had been specifically invalidated. We found that (1) the selective inactivation of ERα in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ERα has no effect; (2) the selective activation of membrane ERα does not prevent neointimal hyperplasia; and (3) ERαAF1 is necessary and sufficient to inhibit postinjury VSMC proliferation. Altogether, ERαAF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ERα largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ERα subfunctions and helps to delineate the spectrum of action of selective ER modulators.

Femoral artery injury during aneurysm coiling.

Femoral artery injury during aneurysm coiling.

Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation.

Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1 deficiency on vascular remodeling in vivo. Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1(+/+) mice (Epac1(+/+)-ASMCs), whereas there was only a 1.2-fold increase in Epac1(-/-)-ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca(2+) was smaller in Fura2-labeled Epac1(-/-)-ASMCs than in Epac1(+/+)-ASMCs. In Epac1(+/+)-ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca(2+) signaling, whereas these effects were rarely observed in Epac1(-/-)-ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1(+/+) mice, whereas neointima formation was significantly attenuated in Epac1(-/-) mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1(+/+) into Epac1(-/-) mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation. These data suggest that Epac1 deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca(2+) influx and a suppression of cofilin-mediated lamellipodia formation occur.

A mobile minimally invasive interventional shelter: a new answer to on-spot emergency treatment of large arterial injuries?

BackgroundSeverely destructive disasters can often lead to heavy casualties. Large arterial injury in disasters, particularly, often results in high mortality and morbidity. Although minimally invasive intervention has achieved positive effects in diagnosing and treating vascular injuries, it is still unavailable at the disaster area of any country due to lack of on-spot catheterization labs. This study aimed to test the feasibility of adopting interventional techniques to treat haemorrhage of large arterial injuries in remote and austere wild environments after severely destructive disasters, by using a new mobile intervention suite we developed—the mobile minimally invasive interventional shelter (MIS).MethodsLarge animal models of aortic and femoral arterial injuries were established using a newly developed medium vehicle-mounted digital subtraction angiography (DSA) machine in MIS. The endovascular stent-graft exclusion and balloon occlusion combined with surgical hemostasis were performed respectively following the protocols for rapid interventional therapy. The treatment capacity of the shelter was evaluated based on its stability, surgery duration and the clinical results.Results and discussionThe stability of the medical devices in MIS directly relates to the efficiency and success rate of interventional treatment. The newly developed vehicle-mounted DSA machine showed good imaging performance and the operation of all equipments and devices in MIS were stable in interventional procedures. All the interventional treatments for large arterial injuries were performed smoothly. The average time for treating abdominal aortic injury and femoral arterial injury was 23 ± 11 and 55 ± 17 min, respectively. And the operation success rate reached 100 %.ConclusionIt is feasible to perform interventional operations to control haemorrhage of large arterial injuries in MIS outside hospital. The MIS has a great potential to save patients from dying of hemorrhagic shock due to lack of effective treatment devices and approaches in remote and austere wild environments, such as in disaster areas.

The safety and feasibility of minimally invasive plate osteosynthesis (MIPO) on the medial side of the femur: A cadaveric injection study

IntroductionMinimally invasive plate osteosynthesis (MIPO) on the medial side of the femur appears to be a dangerous procedure due to possible femoral artery injury. ObjectiveThis study aims to determine the feasibility of applying MIPO of the femur via the medial approach, and to determine the anatomical relationship and structures at risk between the artery and the implant using computed tomography angiography. Materials and methodsA descriptive study of ten fresh cadavers was done. Two separate incisions were made, creating a submuscular tunnel close to the medial side of the femur. An 11- or 13-hole LCP lateral proximal tibial plate (5.0mm) was inserted through the distal incision into the submuscular tunnel and fixed. A CT angiogram with 3D reconstruction was made to determine the distance from and location of the plate relative to the femoral artery and surgical dissection was done to identify the structures at risk. ResultsNo disruptions of superficial or deep femoral arteries were found. The closest distances from the superficial femoral artery and deep femoral artery to the plate were 8.3–27.2mm (average 16.3mm) (99% CI: 12.7–19.9) at the level 3 and 4.5–20.0mm (average 8.6mm) (99% CI: 6.4–10.9) at the level 2 in the proximal part of femur, respectively. The location where the SFA crossed the anterior cortex of the femur in the sagittal plane was 9.7–36.0% of the femoral length (average 20.1%) (99% CI: 15.0–25.3%) and the posterior cortex of the femur was 24.7–55.3% of the femoral length (average 40.8%) (99% CI: 35.0–46.7%). The location where the DFA crossed the anterior cortex of the femur in the sagittal plane was 7.9–25.3% of the femoral length (average 13.4%) (99% CI: 10.6–16.3%) and where it crossed the posterior cortex of the femur was 21.7–39.4% of the femoral length (average 31.2%) (99% CI: 27.1–33.3%). ConclusionMIPO of the femur via medial approach is a feasible option for treatment of femoral fractures when the lateral approach is contraindicated. The distal 60% of the femoral length is safe for this approach.

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling.

Smooth muscle cell (SMC) migration and proliferation play an essential role in neointimal formation after vascular injury. In this study, we intended to investigate whether the X-box-binding protein 1 (XBP1) was involved in these processes. In vivo studies on femoral artery injury models revealed that vascular injury triggered an immediate upregulation of XBP1 expression and splicing in vascular SMCs and that XBP1 deficiency in SMCs significantly abrogated neointimal formation in the injured vessels. In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor β and the inositol-requiring enzyme 1α. The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). XBP1s directed the transcription of mir-1274B that targeted CNN1 mRNA degradation. Proteomic analysis of culture media revealed that XBP1s decreased transforming growth factor (TGF)-β family proteins secretion via transcriptional suppression. TGF-β3 but not TGF-β1 or TGF-β2 attenuated XBP1s-induced CNN1 decrease and SMC proliferation. This study demonstrates for the first time that XBP1 is crucial for SMC proliferation via modulating the platelet-derived growth factor/TGF-β pathways, leading to neointimal formation.

Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation

AimsIt is still controversial whether bone marrow (BM)-derived endothelial progenitor cells (EPCs) can contribute to vascular repair and prevent the progression of vascular diseases. We aimed to characterize BM-derived EPC subpopulations and to evaluate their therapeutic efficacies to repair injured vascular endothelium of systemic and pulmonary arteries. Methods and resultsBM mononuclear cells of Fisher-344 rats were cultured under endothelial cell-conditions. Early EPCs appeared on days 3–6. Late-outgrowth and very late-outgrowth EPCs (LOCs and VLOCs) were defined as cells forming cobblestone colonies on days 9–14 and 17–21, respectively. Among EPC subpopulations, LOCs showed the highest angiogenic capability with enhanced proliferation potential and secretion of proangiogenic proteins. To investigate the therapeutic effects of these EPCs, Fisher-344 rats underwent wire-mediated endovascular injury in femoral artery (FA) and were concurrently injected intraperitoneally with 60mg/kg monocrotaline (MCT). Injured rats were then treated with six injections of one of three EPCs (1×106 per time). After 4weeks, transplanted LOCs, but not early EPCs or VLOCs, significantly attenuated neointimal lesion formation in injured FAs. Some of CD31+ LOCs directly replaced the injured FA endothelium (replacement ratio: 11.7±7.0%). In contrast, any EPC treatment could neither replace MCT-injured endothelium of pulmonary arterioles nor prevent the progression of pulmonary arterial hypertension (PAH). LOCs modified protectively the expression profile of angiogenic and inflammatory genes in injured FAs, but not in MCT-injured lungs. ConclusionBM-derived LOCs can contribute to vascular repair of injured systemic artery; however, even they cannot rescue injured pulmonary vasculature under MCT-induced PAH.