Injured Arteries Research Articles

Abstract 4124604: Finding the Right Course: Unknown Source of Hemorrhage Following Endocardial-Epicardial Ablation for Ventricular Tachycardia

Background: Epicardial radiofrequency ablation via percutaneous access is a common technique for ventricular tachycardia (VT) ablation. Rapid identification of and response to complications can reduce morbidity and mortality. Objective: We present a case of epicardial VT ablation complicated by a distal left internal mammary artery (LIMA) transection secondary to subxiphoid sheath insertion. Report: A 66-year-old man with hypertrophic cardiomyopathy was referred for endo-epicardial ablation of recurrent VT. Pericardial access was obtained using coronary vein exit and carbon dioxide insufflation technique. An 8.5F sheath was advanced over an indwelling pericardial wire, and ablation was performed. Following ablation, 400cc of blood was aspirated from the pericardial space after replacing the 8.5F sheath with a standard pericardial drain. Urgent angiography revealed intact coronary arteries, coronary sinus (CS) and LIMA. The 8.5F sheath was re-introduced and bleeding ceased. CT scan revealed no myocardial or great vessel damage. Mild pericardial drainage continued overnight. The next day, IR angiography demonstrated transection of the distal LIMA from the indwelling sheath. The patient underwent placement of a back-up pericardial drain, followed by coil embolization of the injured artery without complication (Fig). Conclusion: This case highlights the importance of maintaining a broad differential during apparent complications of epicardial access and the importance of staying close to midline for epicardial puncture given anatomic variability. The differential for acute blood loss and pericardial effusion following epicardial ablation includes 1) coronary artery damage, 2) CS damage, 3) extracardiac vascular injury, and 4) right ventricular injury. When extracardiac vascular injury is suspected, multidisciplinary collaboration is essential.

Hyperacute thrombosis of a vertebral artery stent with a single missed dose of a P2Y12 inhibitor and poor stent wall apposition: illustrative case.

Iatrogenic vertebral artery injury during surgery can cause pseudoaneurysm, hemorrhage, thrombosis, ischemia, or death. Strategies to prevent cerebrovascular embolic complications include surgical ligation, endovascular stenting, and/or antiplatelet therapy. A 73-year-old female with a known right vertebral artery occlusion underwent a C2-3 laminectomy, complicated by left vertebral artery injury and occlusion with subsequent posterior circulation ischemia. She underwent immediate angioplasty and stenting of the injured artery with undersized drug-eluting stents. Dual antiplatelet therapy of aspirin 81 mg daily and ticagrelor 90 mg twice daily was initiated. On two occasions, more than 6 months after stenting, holding a single ticagrelor dose led to in-stent thrombosis and embolic stroke within hours of the missed dose. Lifelong therapy with ticagrelor was favored over further procedural intervention. It is recommended to prioritize optimal wall stent apposition with oversized stents in patients without collateral circulation. The risk of thromboembolism due to poorly apposed stents is very high, even in delayed (> 6 months) settings. Stent construct revision or bypass grafting may not be feasible or desirable options. For patients without wall apposition, endothelialization may not occur, necessitating lifelong P2Y12 inhibitor therapy to prevent recurrent thromboembolic events. https://thejns.org/doi/10.3171/CASE24296.

Impact of proNGF/NGF-NGFR-axis on the regulation of arterial remodelling

Abstract Background Peripheral blood mononuclear cells (MNCs) contribute to the pathogenesis of arteriosclerosis. Nerve growth factor receptor (NGFR) is present in peripheral blood and the ischemic coronary artery. NGFR transduces neurotrophin signals towards cell survival or apoptosis in different cell types dependent on coupling co-receptors. However, the role of NGFR-positive (NGFR+) MNCs in arterial remodelling is unknown. Purpose To investigate the functional mechanisms under which NGFR+ MNCs are involved in arterial remodelling. Methods Adult C57BL/6J male NGFR-wild-type (WT) or -bone marrow (BM)-specific (KO) mice were subjected to unilateral carotid artery ligation. The ligated and the opposite-sided, sham-operated arteries were assessed by immunohistology and gene expression analysis using a PCR on day 28. Also, human NGFR+ MNCs from a healthy volunteer were sorted using fluorescence-activated cell sorting and characterised using RNA sequencing. The cell apoptosis (AnnexinV+7AAD-) and chemotaxis in response to the ligands, NGF and its precursor proNGF, were assessed using flow cytometry and a Transwell migration. Results In WT mice, BM-derived NGFR+ cells accumulated in the neointima after ligation. The neointimal area was significantly greater in the BM-specific depletion of NGFR than in WT mice. NGFR+ cells in the neointima exhibited apoptosis (TUNEL+ and cleaved caspase-3+) accompanied by promoted F4/80+ macrophage and anti-inflammatory IL-10. By contrast, in the BM-specific NGFR-KO model, non-BM-derived SMCs increased in the neointima with augmented proliferation, and the accumulation of BM-derived cells and the expression of IL-10 were decreased. The expressions of proNGF/NGF and inflammatory cytokines, including IL-6, were not changed in a ligated artery, irrespective of NGFR+ depletion. Human NGFR+ MNCs expressed TrkB, TrkC, and sortilin co-receptors but not macrophage markers. Human NGFR+ MNCs, but not NGFR- MNCs, co-cultured with artery SMCs were susceptible to apoptosis in response to proNGF. Additionally, PDGF stimulated proNGF/NGF expression in SMCs, and proNGF/NGF did not affect the proliferation of SMCs in vitro. Furthermore, NGFR+ MNCs, but not NGFR- MNCs, increased migration toward NGF and did not show chemotaxis toward proNGF. Conclusions These data imply that local NGF might draw NGFR+ MNCs to the injured artery, in which proNGF induces NGFR+ MNCs apoptosis. Apoptotic NGFR+ cells promoted macrophage chemotaxis to resolve inflammation and decrease neointimal formation. Thus, we propose the proNGF/NGF-NGFR axis as potentially contributing to the suppression of arterial remodelling.

Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation.

CRP (C-reactive protein) is a prototypical acute phase reactant. Upon dissociation of the pentameric isoform (pCRP [pentameric CRP]) into its monomeric subunits (mCRP [monomeric CRP]), it exhibits prothrombotic and proinflammatory activity. Pathophysiological shear rates as observed in aortic valve stenosis (AS) can influence protein conformation and function as observed with vWF (von Willebrand factor). Given the proinflammatory function of dissociated CRP and the important role of inflammation in the pathogenesis of AS, we investigated whether shear stress can modify CRP conformation and induce inflammatory effects relevant to AS. To determine the effects of pathological shear rates on the function of human CRP, pCRP was subjected to pathophysiologically relevant shear rates and analyzed using biophysical and biochemical methods. To investigate the effect of shear on CRP conformation in vivo, we used a mouse model of arterial stenosis. Levels of mCRP and pCRP were measured in patients with severe AS pre- and post-transcatheter aortic valve implantation, and the presence of CRP was investigated on excised valves from patients undergoing aortic valve replacement surgery for severe AS. Microfluidic models of AS were then used to recapitulate the shear rates of patients with AS and to investigate this shear-dependent dissociation of pCRP and its inflammatory function. Exposed to high shear rates, pCRP dissociates into its proinflammatory monomers (mCRP) and aggregates into large particles. Our in vitro findings were further confirmed in a mouse carotid artery stenosis model, where the administration of human pCRP led to the deposition of mCRP poststenosis. Patients undergoing transcatheter aortic valve implantation demonstrated significantly higher mCRP bound to circulating microvesicles pre-transcatheter aortic valve implantation compared with post-transcatheter aortic valve implantation. Excised human stenotic aortic valves display mCRP deposition. pCRP dissociated in a microfluidic model of AS and induces endothelial cell activation as measured by increased ICAM-1 and P-selectin expression. mCRP also induces platelet activation and TGF-β (transforming growth factor beta) expression on platelets. We identify a novel mechanism of shear-induced pCRP dissociation, which results in the activation of cells central to the development of AS. This novel mechanosensing mechanism of pCRP dissociation to mCRP is likely also relevant to other pathologies involving increased shear rates, such as in atherosclerotic and injured arteries.

Silencing of PCK1 mitigates the proliferation and migration of vascular smooth muscle cells and vascular intimal hyperplasia by suppressing STAT3/DRP1-mediated mitochondrial fission.

The pathological proliferation and migration of vascular smooth muscle cells (VSMCs) are key processes during vascular neointimal hyperplasia (NIH) and restenosis. Phosphoenolpyruvate carboxy kinase 1 (PCK1) is closely related to a variety of malignant proliferative diseases. However, the role of PCK1 in VSMCs has rarely been investigated. This study aims to examine the role of PCK1 in the proliferation and migration of VSMCs and vascular NIH after injury. In vivo, extensive NIH and increased expression of PCK1 within the neointima are observed in injured arteries. Interestingly, the administration of adeno-associated virus-9 (AAV-9) carrying Pck1 short hairpin RNA (sh Pck1) significantly attenuates NIH and stenosis of the vascular lumen. In vitro, Pck1 small interfering RNA (si Pck1)-induced PCK1 silencing inhibits VSMC proliferation and migration. Additionally, silencing of PCK1 leads to reduced expression of dynamin-related protein 1 (DRP1) and attenuated mitochondrial fission. Lentivirus-mediated DRP1 overexpression markedly reverses the inhibitory effects of PCK1 silencing on VSMC proliferation, migration, and mitochondrial fission. Finally, PCK1 inhibition attenuates the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Activation of STAT3 abolishes the suppressive effects of PCK1 silencing on DRP1 expression, mitochondrial fission, proliferation, and migration in VSMCs. In conclusion, PCK1 inhibition attenuates the mitochondrial fission, proliferation, and migration of VSMCs by inhibiting the STAT3/DRP1 axis, thereby suppressing vascular NIH and restenosis.

Enhanced Targeted Repair of Vascular Injury by Apoptotic‐Cell‐Mimicking Nanovesicles Engineered with P‐Selectin Binding Peptide

AbstractModulating inflammation is crucial for repairing vascular injury. Phagocytosis of apoptotic cells represents an effective mechanism for attenuating inflammation and improving regeneration during natural healing. However, strategies for repairing vascular injuries using biomaterials derived from apoptotic cells are still undeveloped. Herein, apoptotic body‐mimetic nanovesicles (ApoNVs) derived from rat adipose‐derived mesenchymal stem cells (rASCs) are prepared using a one‐step extrusion method. ApoNVs inherit the unique anti‐inflammatory and pro‐regenerative properties of the parental apoptotic rASCs, as evidenced by enhanced M2 polarization of macrophages and promoted endothelial cell proliferation and migration following treatment with ApoNVs. Moreover, ApoNVs enhance the contractile phenotype of vascular smooth muscle cells through the mediation of ApoNVs‐induced repolarized macrophages. After engineering ApoNVs with P‐selectin binding peptide (ApoNVs‐PBP), their ability to target injured artery increased nearly sevenfold compared to unmodified ApoNVs. In a rat wire‐mediated femoral artery injury model, ApoNVs‐PBP effectively suppress inflammation and significantly reduce blood flow velocity and neointimal hyperplasia at the injury site. ApoNVs exhibit similar therapeutic effects, though to a lesser extent. This study provides strong evidence validating the targeted delivery of ApoNVs as an innovative approach for repairing vascular injury and highlights their potential in treating other inflammatory diseases.

Application of flow-through flaps for replantation after traumatic limb amputation according to the angiosome concept.

This study was performed to explore the treatment of the injury caused by traumatic limb amputation. From October 2002 to October 2021, 30 cases were enrolled in the present study. The reasons for injury were as follows: 8 cases with single hydraulic column crush injury, 12 cases with gear and wire rope stranding, 6 cases with belt avulsion injury, and 4 cases with carbon block smash injury. The present study application of a free or small saphenous vein bypass to reconstruct the injured artery and vein according to the concept of the angiosome model. The defective vessels were bridged with the axial vessels of a flow-through flap, such as a medial calf flap or anterolateral femoral flap, to construct an additional blood supply and drainage vein for the severed limb. The clinical data of 30 cases with traumatic limb amputation of the lower leg and ankle were retrospectively analyzed. In all 30 cases of traumatic limb amputation, the replantation via the adoption of a flow-through flap was successful, and 85.6% of the patients remained in good postoperative condition. There were no symptoms of ischemia in the marginal segment after blood supply reconstruction of the transected limb by axial vascular bridging within the flap. Via the adoption of microsurgical techniques, the blood supply to the transected limb can be reconstructed by bridging the defective vessels with the adoption of the axial vessels of the flow-through flap is a feasible and advanced treatment option.

Reduced platelet activation and thrombus formation in male transgenic model mice of Alzheimer's disease suggests early sex-specific differences in platelet pathophysiology

Alzheimer's disease (AD) is the most common form of dementia and characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles and neurodegeneration. Over 80 % of AD patients also exhibit cerebral amyloid angiopathy (CAA). CAA is a cerebrovascular disease caused by deposition of Aβ in the walls of cerebral blood vessels leading to vessel damage and impairment of normal blood flow. To date, different studies suggest that platelet function, including activation, adhesion and aggregation, is altered in AD due to vascular Aβ deposition. For example, the transgenic AD model mice APP23 mice that exhibit CAA and parenchymal Aβ plaques, show pre-activated platelets in the blood circulation and increased platelet integrin activation leading to a pro-thrombotic phenotype in these mice late stages of AD. However, it is still an open question whether or not platelets exhibit changes in their activation profile before they are exposed to vascular Aβ deposits. Therefore, the present study examined platelets from middle-aged transgenic APP23 mice at the age of 8–10 months. At this age, APP23 mice show amyloid plaques in the brain parenchyma but not in the vasculature. Our analyses show that these APP23 mice have unaltered platelet numbers and size, and unaltered surface expression of glycoproteins. However, the number of dense granules in transgenic platelets was increased while the release was unaltered. Male, but not female APP23 mice, exhibited reduced platelet activation after stimulation of the thrombin receptor PAR4 and decreased thrombus stability on collagen under flow conditions ex vivo compared to control mice. In an arterial thrombosis model in vivo, male APP23 mice showed attenuated occlusion of the injured artery compared to controls. These findings provide clear evidence for early changes in platelet activation and thrombus formation in male mice before development of overt CAA. Furthermore, reduced platelet activation and thrombus formation suggest sex-specific differences in platelet physiology in AD that has to be considered in future studies of platelets and their role in AD.

Intervention of Asprosin Attenuates Oxidative Stress and Neointima Formation in Vascular Injury.

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury. Antioxid. Redox Signal. 41, 488-504.

Inhibition of CIRBP represses the proliferation and migration of vascular smooth muscle cells via inhibiting Rheb/mTORC1 axis

The excessive migration and proliferation of vascular smooth muscle cells (VSMCs) plays a vital role in vascular intimal hyperplasia. CIRBP is involved in the proliferation of various cancer cells. This study was aimed to explore the role of CIRBP in the proliferation and migration of VSMCs. Adenovirus was used to interfere with cold-inducible RNA-binding protein (CIRBP) expression, while lentivirus was used to overexpress Ras homolog enriched in brain (Rheb). Western blotting and qRT-PCR were used to evaluate the expression of CIRBP, Rheb, and mechanistic target of rapamycin complex 1 (mTORC1) activity. The cell proliferation was determined by Ki67 immunofluorescence staining and CCK-8 assay. The wound healing assay was performed to assess cell migration. Additionally, immunohistochemistry was conducted to explore the role of CIRBP in intimal hyperplasia after vascular injury. We found that silencing CIRBP inhibited the proliferation and migration of VSMCs, decreased the expression of Rheb and mTORC1 activity. Restoration of mTORC1 activity via insulin or overexpression of Rheb via lentiviral transfection both attenuated the inhibitory effects of silencing CIRBP on the proliferation and migration of VSMCs. Moreover, Rheb overexpression abolished the inhibitory effect of silencing CIRBP on mTORC1 activity in VSMCs. CIRBP was upregulated in the injured carotid artery. Silencing CIRBP ameliorated intimal hyperplasia after vascular injury. In the summary, silencing CIRBP attenuates mTORC1 activity via reducing Rheb expression, thereby supressing the proliferation and migration of VSMCs and intimal hyperplasia after vascular injury.

Platelet-endothelial aggregation receptor 1 inhibits reendothelialization of injured arteries

Platelet-endothelial aggregation receptor 1 inhibits reendothelialization of injured arteries

Intraplatelet Calcium Signaling Regulates Thrombus Growth under Flow: Insights from a Multiscale Model

In injured arteries, platelets adhere to the subendothelium and initiate the coagulation process. They recruit other platelets and form a plug that stops blood leakage. The formation of the platelet plug depends on platelet activation, a process that is regulated by intracellular calcium signaling. Using an improved version of a previous multiscale model, we study the effects of changes in calcium signaling on thrombus growth. This model utilizes the immersed boundary method to capture the interplay between platelets and the flow. Each platelet can attach to other platelets, become activated, express proteins on its surface, detach, and/or become non-adhesive. Platelet activation is captured through a specific calcium signaling model that is solved at the intracellular level, which considers calcium activation by agonists and contacts. Simulations reveal a contact-dependent activation threshold necessary for the formation of the thrombus core. Next, we evaluate the effect of knocking out the P2Y and PAR receptor families. Further, we show that blocking P2Y receptors reduces platelet numbers in the shell while slightly increasing the core size. An analysis of the contribution of P2Y and PAR activation to intraplatelet calcium signaling reveals that each of the ADP and thrombin agonists promotes the activation of platelets in different regions of the thrombus. Finally, the model predicts that the heterogeneity in platelet size reduces the overall number of platelets recruited by the thrombus. The presented framework can be readily used to study the effect of antiplatelet therapy under different physiological and pathological blood flow, platelet count, and activation conditions.

Differential Distribution and Expression of α1-adrenergic Receptors in Low Shear Stress Induced Neointimal Formation

Low fluid shear stress in conduit arteries has emerged as a determinant of neointimal formation—an accumulation of vascular smooth muscle cells on the surface of the intima—the most challenging component of atherosclerosis to treat. α1-adrenergic receptor (α1-AR) antagonists have been well evaluated in vascular injury models yielding reduced neointimal formation. However, the α1-AR subtypes’ (α1A-AR, α1B-AR, α1D-AR) role in neointimal formation have not been determined under low shear stress conditions. α1-AR subtypes are expressed in various tissues and evoke different responses to the same ligand resulting in both adaptive and maladaptive responses. This study was designed to identify and characterize the α1-AR subtypes in low shear stress induced neointimal formation. An in vivo partial ligation mouse model was utilized to actuate low fluid shear stress and create neointimal formation in the left carotid artery in 14 days. The right carotid artery remained uninjured as the control. For tissue collection and processing, the left and right carotid arteries were harvested, snap-frozen in liquid nitrogen, and cryosectioned. Immunofluorescence staining was performed using primary antibodies for α1B-AR or α1A-AR and CD31 (endothelial cell marker). Confocal microscopy combined with processing and analysis was utilized for the detection, location, and distribution of cell markers. Histomorphometric analysis revealed significant structural changes, including the medial area and neointimal area, between the injured and non-injured arteries at the 14-day timepoint. Moreover, the injured arteries showed an increase in percent area stenosis, compared to the non-injured control. Histological observation of fluorescently labeled images revealed α1B-AR is densely distributed in the neointimal and medial area of the injured carotid arteries compared to the non-injured control. NucBlue (nuclear) staining indicated an increase in cell number in the medial and neointimal areas of the injured artery. Together, these results offer insight into changes in vascular α1-ARs under low shear stress conditions suggesting that α1B-AR may be upregulated in response to injury and contribute to neointimal formation. NIH HL155288. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 3137: The Role Of Rna Binding Protein Fxr1 In Regulating Methylated Mrna Transcript Stability And Vascular Smooth Muscle Cell Contractility

Introduction/Background: A dysregulation in vascular smooth muscle cell (VSMC) cytoskeletal components may contribute to impaired contraction, leading to vascular disease. Post-transcriptional mechanisms of mRNA stability is an understudied, yet key mechanism in the regulation of VSMC contractility. m6A mRNA methylation is the most prevalent post-transcriptional modification and recognized to regulate mRNA stability. We recently showed that inducible expression of RNA binding protein FXR1 in injured arteries and stimulated hVSMCs regulates VSMC cytoskeletal gene mRNA stability, and FXR1 smc/smc mice have decreased VSMC contractility and blood pressure. Research Questions/Hypothesis: FXR1 functions as an m6A mRNA reader and regulates the stability of m6A methylated transcripts, altering VSMC contractility. Goals/Aims: To determine if the m6A methylation of mRNA transcripts by m6A methylases METTL3 and METTL14 play an important role in regulating cytoskeletal mRNA abundance and VSMC contractility and if transcript recognition by FXR1 is modified by transcript methylation state. Methods/Approach: m6A profiling was performed to investigate methylation status of hVSMC mRNA transcripts. Contraction assay following knockdown of METTL3 was performed to assess VSMC contraction. RNA immunoprecipitation experiments were performed to identify FXR1- interacting cytoskeletal transcripts following METTL3 knockdown. Biotinylated pulldown experiments were performed to assess FXR1’s interaction with methylated RNA probes. Results/Data: Cytoskeletal-related mRNA are the most highly methylated category of methylated transcripts. FXR1 interacts with methylated rather than unmodified target probes. Knockdown of the m6A methylase, METTL3 resulted in significantly decreased contraction of hVSMC. METTL3 knockdown significantly reduced FXR1-cytoskeletal mRNA interactions. Conclusions: These data support our hypothesis that FXR1 is an m6A methylated mRNA reader which regulates cytoskeletal mRNA stability and VSMC contractility.

Small nucleolar RNA host gene 18 controls vascular smooth muscle cell contractile phenotype and neointimal hyperplasia.

Long non-coding RNA (LncRNA) small nucleolar RNA host gene 18 (SNHG18) has been widely implicated in cancers. However, little is known about its functional involvement in vascular diseases. Herein, we attempted to explore a role for SNHG18 in modulating vascular smooth muscle cell (VSMC) contractile phenotype and injury-induced neointima formation. Analysis of single-cell RNA sequencing and transcriptomic datasets showed decreased levels of SNHG18 in injured and atherosclerotic murine and human arteries, which is positively associated with VSMC contractile genes. SNHG18 was upregulated in VSMCs by TGFβ1 through transcription factors Sp1 and SMAD3. SNHG18 gene gain/loss-of-function studies revealed that VSMC contractile phenotype was positively regulated by SNHG18. Mechanistic studies showed that SNHG18 promotes a contractile VSMC phenotype by up-regulating miR-22-3p. SNHG18 up-regulates miR-22 biogenesis and miR-22-3p production by competitive binding with the A-to-I RNA editing enzyme, adenosine deaminase acting on RNA-2 (ADAR2). Surprisingly, we observed that ADAR2 inhibited miR-22 biogenesis not through increasing A-to-I editing within primary miR-22, but by interfering with the binding of microprocessor complex subunit DGCR8 to primary miR-22. Importantly, perivascular SNHG18 overexpression in the injured vessels dramatically up-regulated the expression levels of miR-22-3p and VSMC contractile genes, and prevented injury-induced neointimal hyperplasia. Such modulatory effects were reverted by miR-22-3p inhibition in the injured arteries. Finally, we observed a similar regulator role for SNHG18 in human VSMCs and a decreased expression level of both SNHG18 and miR-22-3p in diseased human arteries; and we found that the expression level of SNHG18 was positively associated with that of miR-22-3p in both healthy and diseased human arteries. We demonstrate that SNHG18 is a novel regulator in governing VSMC contractile phenotype and preventing injury-induced neointimal hyperplasia. Our findings have important implications for therapeutic targeting snhg18/miR-22-3p signalling in vascular diseases.

Resveratrol Inhibits Restenosis through Suppressing Proliferation, Migration and Trans-differentiation of Vascular Adventitia Fibroblasts via Activating SIRT1.

After the balloon angioplasty, vascular adventitia fibroblasts (VAFs), which proliferate, trans-differentiate to myofibroblasts and migrate to neointima, are crucial in restenosis. Resveratrol (RSV) has been reported to protect the cardiovascular by reducing restenosis and the mechanism remains unclear. This study was dedicated to investigate the effect of RSV on VAFs in injured arteries and explore the potential mechanism. In this work, carotid artery balloon angioplasty was performed on male SD rats to ensure the injury of intima and VAFs were isolated to explore the effects in vitro</i>. The functional and morphological results showed the peripheral delivery of RSV decreased restenosis of the injured arteries and suppressed the expression of proliferation, migration and transformation related genes. Moreover, after being treated with RSV, the proliferation, migration and trans-differentiation of VAFs were significantly suppressed and exogenous TGF-β1 can reverse this effect. Mechanistically, RSV administration activated SIRT1 and decreased the translation and expression of TGF-β1, SMAD3 and NOX4, and reactive oxygen species (ROS) decreased significantly after VAFs treated with RSV. Above results indicated RSV inhibited restenosis after balloon angioplasty through suppressing proliferation, migration and trans-differentiation of VAFs via</i> regulating SIRT1- TGF-β1-SMAD3-NOX4 to decrease ROS.

Analysis of Punch Injuries: Clinical Characteristics, Management and Outcomes.

The aim of this study is to describe injury patterns, characteristics, treatment modalities and functional outcomes after punching related injuries. Retrospective data of cases admitted to emergency department following punch injury between January 1, 2012, and December 31, 2022. was collected. Patient's demographic data, the dominant and injured upper extremity side, punched object, a time of patient admission were recorded. Smoking habit and blood ethanol level were documented. Trauma mechanism, diagnosis (1: dermabrasions: skin, 2: lacerations: neurovascular structures or tendons and 3: osseous pathologies), treatment modalities were analyzed. Outcomes were assessed using the DASH questionnaire (Disabilities of the Arm, Shoulder, and Hand) at the last follow-up. A total of 1052 patients (male=968 (92%), female=84 (8%)) with mean age 24.6 ± 7.2 included this study. Six hundred and twenty-one (59%) patients punched a solid object and 675 (64%) had osseous pathology. The most commonly fractured bone, injured tendon, injured nerve, and injured artery were 5th metacarpal, extensor digitorum communis (EDC), ulnar nerve, and ulnar artery, respectively. The majority of the patients, (73%) were smokers while 15% of the patients had high level of blood ethanol concentration on admission (82±12.3 mg/100 ml). A comparison between smokers and non-smokers did not reveal any significant differences (p=0.425) in terms of diagnosis whereas 74% of alcoholic patients admitted with lacerations which was statistically significant (p=0.023). Injuries of 321 (30.5%) patients required surgery in the operating room, while 711(67.5 %) patients received interventions in the emergency room setting. The average DASH score differed between subgroups, with significantly higher scores in patients with laceration type injuries (7.2 SD), indicating more disability (p=0.001) DISCUSSION. The study reveales a high prevalence of hand injuries among individuals aged 18 to 40, with the dominant hand being most affected, primarily due to physical violence and self-harming behaviors. Primary contributing factors to this pattern are the escalated incidents of physical violence and self-harming behaviors arising from an inability to manage anger impulses. Punching solid objects, especially during late afternoon and evening periods often associated with alcohol use, was a common cause, resulting in metacarpal fractures being the most reported injury. Multiple tendon and nerve injuries were frequent, highlighting the severity and complexity of these traumas, often necessitating surgical intervention. These findings highlight the several key aspects, including demographic characteristics of the patient population, common causes and types of injuries observed, and the association between alcohol use as well as the specific injury profiles. Satisfactory results can be achieved with both conservative and surgical treatment for punch injuries. punching, fisting, boxing injuries, laceration, blood ethanol level.

A Tubular Vena Cava Conduit Used to Lengthen a Kidney Transplant Renal Artery Injured During Organ Procurement

Organ transplantation is limited by the supply of transplantable organs, and the supply of organs cannot meet the needs of patients on the waiting list. Ensuring transplantation of any procured organ is therefore mandatory. Organ injury, mostly to the organ's vasculature, can occur during multi-organ procurement, preventing subsequent transplantation. In such a context, vascular reconstructions of arterial or venous organ injuries can be useful. This report describes the case of an obese 64 year old female with a history of diabetic nephropathy who underwent a cadaveric kidney transplant (right kidney with one main renal artery, one inferior polar artery, one vein, and one ureter). The ex situ preparation of the graft revealed that the main renal artery was injured and cut close to the renal hilum (0.8 cm length, 6 mm diameter), not allowing graft implantation. In order to increase the length of the main renal artery, the donor inferior vena cava was used to create a tubular conduit, allowing subsequent graft implantation. Cold and warm ischaemic times were respectively 12 hours and 36 minutes, with immediate graft function. The patient was discharged on day 8 (serum creatinine level was 95 μmol/L). Twelve month follow up was uneventful (serum creatinine level was 108 μmol/L and duplex ultrasonography showed homogeneous blood flow throughout the graft). This case report highlights the possibility of overcoming an injured kidney graft artery by creating a tubular vena cava conduit in order to allow subsequent transplantation. Vascular reconstructions of organs injured during procurement should be considered.

Nitric oxide transport in carotid bifurcation after different stent interventions: a numerical study

Stent restenosis and late thrombosis compromise endovascular stent implantation clinical benefit, and the mechanism is unclear. Since nitric oxide (NO) plays a pivotal role in maintaining vascular homeostasis, we believe that stenting can affect NO concentration in the host artery, thereby contributing to postoperative adverse events. We numerically investigated NO concentration after stenting based on the patient-specific carotid to verify this hypothesis. The simulation revealed that stent implantation caused blood flow disturbance, a low wall shear stress, and a significant decrease in NO on the luminal surface, especially in the region of the stented segment. Moreover, severe damage to the artery wall or low blood flow, leading to a low NO generation rate, would induce relatively low NO level in the stented segment. Additionally, we demonstrated that NO distribution might be affected by the combination of stent struts and carotid bifurcation geometry, while the host arterial configuration might play a leading role in the distribution of NO concentration. In conclusion, the carotid artery had a relatively low NO concentration level near stent struts, especially at the severely injured artery, low blood flow, long stenting, and complex host artery which might lead to a genesis/development of adverse events after that intervention.

Abstract 17441: Non-Invasive Quantification of Peripheral Angioplasty-Induced Vascular Inflammation in a Porcine Model Using PET/CT Imaging

Background: Similarities in peripheral vascular anatomy between swine and humans make this animal an ideal model for evaluating the effects of lower extremity angioplasty procedures commonly performed to improve limb blood flow in peripheral artery disease (PAD). Hypothesis: We hypothesized that PET/CT imaging would provide a non-invasive strategy for quantifying the inflammatory response to balloon overdilation injury in a swine model of peripheral angioplasty. Methods: Five Yorkshire pigs (weight = 25 kg) underwent overdilation of the right femoral artery. A balloon catheter (7 mm x 40 mm) was introduced via the carotid artery and guided to the femoral artery under fluoroscopy. The balloon was then inflated to a pressure 1.5 times greater the recommended nominal pressure to induce arterial injury. 18 F-fluorodeoxyglucose (FDG) PET/CT imaging was performed 14 days after angioplasty to quantify in vivo inflammation in the injured and control femoral arteries, which was expressed as the maximum standardized uptake value (SUV max ). Pigs were euthanized 14 days post-angioplasty and arteries were harvested and sectioned for gamma counting ( 18 F-FDG uptake), and stained with hematoxylin and eosin histology (H&amp;E), Masson’s trichrome, and alpha-smooth muscle actin (α-SMA) for evaluation of intimal remodeling and smooth muscle cell proliferation. Results: 18 F-FDG PET/CT imaging quantified a significant increase in inflammation for the injured versus control femoral artery 14 days post-angioplasty (p=0.04). Gamma counting confirmed a significant increase in 18 F-FDG uptake in the injured artery (p=0.02). H&amp;E revealed a significant increase in intimal thickening in the injured artery (p=0.03). α-SMA expression was also significantly increased in the injured versus control femoral artery (p=0.01), demonstrating an increase in smooth muscle cell proliferation. Conclusions: 18 F-FDG PET/CT quantifies arterial inflammation resulting from overdilation injury that is associated with intimal remodeling and smooth muscle cell proliferation. PET/CT imaging may provide a non-invasive strategy for in vivo testing of the efficacy of emerging drug-coated endovascular peripheral devices.