Macrophage membrane camouflaged reactive oxygen species responsive nanomedicine for efficiently inhibiting the vascular intimal hyperplasia

Background Intimal hyperplasia caused by vascular injury is an important pathological process of many vascular diseases, especially occlusive vascular disease. In recent years, Nano-drug delivery system has attracted a wide attention as a novel treatment strategy, but there are still some challenges such as high clearance rate and insufficient targeting. Results In this study, we report a biomimetic ROS-responsive MM@PCM/RAP nanoparticle coated with macrophage membrane. The macrophage membrane with the innate “homing” capacity can superiorly regulate the recruitment of MM@PCM/RAP to inflammatory lesion to enhance target efficacy, and can also disguise MM@PCM/RAP nanoparticle as the autologous cell to avoid clearance by the immune system. In addition, MM@PCM/RAP can effectively improve the solubility of rapamycin and respond to the high concentration level of ROS accumulated in pathological lesion for controlling local cargo release, thereby increasing drug availability and reducing toxic side effects. Conclusions Our findings validate that the rational design, biomimetic nanoparticles MM@PCM/RAP, can effectively inhibit the pathological process of intimal injury with excellent biocompatibility. Graphical Abstract

Superior vena cava syndrome after pacemaker implantation treated with direct oral anticoagulation

Background Superior Vena Cava (SVC) syndrome, is a quite rare but serious complication after pacemaker lead implantation; most patients are asymptomatic due to the development of adequate venous collateral circulation. Case presentation We report a case of a 75-year-old woman who developed SVC syndrome after transvenous pacemaker implantation with complete resolution of the thrombosis after 3 months of oral anticoagulation. Conclusions Generally other causes as malignancy are considered to be the most common etiology of SVC syndrome, but benign iatrogenic causes, mainly intravascular devices (central vein catheters, cardiac defibrillators and pacemaker wires), are becoming increasingly common. Procedures performed on venous vasculature, causing a possible intimal injury or vein stenosis, provoked by transvenous leads, seem to be the most reasonable explanation for the observed complication.

Hemodynamic Principles in Free Tissue Transfer: Vascular Changes at the Anastomosis Site

Purpose: Various factors such as blood velocity, turbulent flow,and intimal injury are the most basic elements in free tissue transfers. However, how blood flow is reestablished, maintained, and changed after vascular anastomosis has rarely been studied.Methods: A 54-year-old male sustained an unreplantable severe crushing injury to his right hand. The middle finger was transferred to the thumb as an ectopic replantation using an anastomosis between the radial and digital arteries. However, secondary reconstruction for the first web space defect was inevitable and an anteromedial thigh free flap procedure was performed 2 months later using the previously anastomosed vessels. During the procedures, we noted morphologic changes in the microvessels and tried to explain those phenomena by applying the principles of hemodynamics.Results: Due to the discrepancy in vascular size between the radial and digital arteries, the velocity of the blood flow in the post-anastomotic site, which was the digital artery, must have been increased by Poiseuille’s law. Supposing that the velocity through the post-anastomotic site of the digital artery was increased, the pressure exerted by that flow decreased, resulting in more shrinkage of the vessel lumen of the digital artery by Bernoulli’s principle. Pascal’s law could also be applied in confined spaces with a static flow; where there is a constant pressure, as the radius of the post-anastomotic digital artery diminishes, the tension within the digital artery’s wall also simultaneously decreases. By Laplace’s law, the post-anastomotic digital artery’s wall thickens as less tension is exerted on the wall.Conclusion: Understanding these simple flow mechanics will enable microsurgeons to better avoid the risk factors causing thrombosis, which is related to flap failure.

Platelet-Derived Microvesicles Promote VSMC Dedifferentiation After Intimal Injury via Src/Lamtor1/mTORC1 Signaling

Phenotypic switch of vascular smooth muscle cells (VSMCs) is important in vascular remodeling which causes hyperplasia and restenosis after intimal injury. Platelets are activated at injured intima and secrete platelet-derived microvesicles (PMVs). Herein, we demonstrated the role of PMVs in VSMC phenotypic switch and the potential underlying mechanisms. In vivo, platelets were locally adhered and activated at intimal injury site, while Lamtor1 was promoted and VSMCs were dedifferentiated. PMVs, collected from collagen-activated platelets in vitro which mimicked collagen exposure during intimal injury, promoted VSMC dedifferentiation, induced Lamtor1 expression, and activated mTORC1 signaling, reflected by the phosphorylation of two downstream targets, i.e., S6K and 4E-BP1. Knockdown of Lamtor1 with small interfering RNA attenuated these processes induced by PMVs. Based on the previously published proteomic data, Ingenuity Pathway Analysis revealed that Src may participate in regulating effects of PMVs. Src inhibitor significantly reversed the effects of PMVs on VSMC dedifferentiation, Lamtor1 expression and mTORC1 activation. Furthermore, in SMC-specific Lamtor1 knockout mice, intimal hyperplasia was markedly attenuated after intimal injury compared with the wild type. Our data suggested that PMVs secreted by activated platelets promoted VSMC dedifferentiation via Src/Lamtor1/mTORC1 signaling pathway. Lamtor1 may be a potential therapeutic target for intimal hyperplasia after injury.

Immunomodulation of IL-33 and IL-37 with Vitamin D in the Neointima of Coronary Artery: A Comparative Study between Balloon Angioplasty and Stent in Hyperlipidemic Microswine

Inflammation is a major contributor to the development and progression of atherosclerosis. Interleukin (IL)-33 and IL-37, members of the IL-1 family, modulate inflammation, with IL-33 having a pro-inflammatory effect and IL-37 having anti-inflammatory properties. IL-37 is constitutively expressed at low levels but upregulated in inflammatory contexts. The aim of this study was to evaluate the effect of vitamin D on the expression of IL-33, IL-37, macrophages, and caspase-1 in the neointimal tissue of coronary artery in Yucatan microswine with vitamin D deficient, sufficient, and supplemented status. The intimal injury was induced by balloon angioplasty and stenting in the coronary artery, and tissues were harvested after 6 months. The expression of various proteins of interest was evaluated by immunostaining. Increased expression of IL-33 and IL-37 in the neointimal tissue of the vitamin D deficient, as compared to the sufficient and supplemented microswine, as revealed by histological evaluation and semi-quantitative analysis, suggested the immunomodulatory effect of vitamin D on the expression of IL-33 and IL-37. The minimal expression or absence of IL-33 and IL-37 expression in stented arteries is suggestive of an attenuated inflammatory response in stented arteries, compared to balloon angioplasty. The decreased IL-33 expression in the sufficient and supplemented microswine could be a potential mechanism for controlling the inflammatory process and neointima formation leading to attenuated luminal narrowing of the coronary artery. Overall, these results support supplementation of vitamin D to attenuate inflammation, neointima formation, and restenosis.

Morphological and Molecular-Biological Changes in the Coronary Arteries after Stenting

This review addresses morphological changes in coronary arteries following stenting, which result from damage to the vascular wall. These changes include 1) formation of a thrombus in the site of intimal injury; 2) inflammation; 3) proliferation and migration of smooth muscle cells; 4) formation of extracellular matrix. Each of these pathological processes has specific morpho-biological features. The review shows the role of von Willebrand factor in development of early thrombosis after intimal injury, which provokes activation of the inflammatory response followed by proliferation of smooth muscle cell that synthetize the extracellular matrix. These cellular and intercellular changes are based on overexpression of TGF-β1 protein, which facilitates modulation of various types of smooth muscle cells, including contractile and secretory ones. Issues of fine regulation of cellular and intercellular interactions by apoptosis, activation of mTOR signaling molecules, and microRNA are still understudied. Dynamic changes in drug-coated stents during development of neoatherosclerosis and late thrombosis remain not elucidated. Current reports show that initial mechanisms triggering pathological regenerative and hyperplastic processes that result in coronary restenosis in the area of implanted stents may form early (first hours or days) after stenting. Most studies were performed on experimental rather than on autopsy material, which does not allow fully unbiased interpretation of obtained data. Studying dynamics of morphological and molecular changes in coronary arteries after stenting, including on autopsy material, will allow one to express an opinion on the risk of postoperative thrombosis and restenosis.

Platelet-Derived Extracellular Vesicles Increase Col8a1 Secretion and Vascular Stiffness in Intimal Injury

The arterial mechanical microenvironment, including stiffness, is a crucial pathophysiological feature of vascular remodeling, such as neointimal hyperplasia after carotid endarterectomy and balloon dilatation surgeries. In this study, we examined changes in neointimal stiffness in a Sprague-Dawley rat carotid artery intimal injury model and revealed that extracellular matrix (ECM) secretion and vascular stiffness were increased. Once the endothelial layer is damaged in vivo, activated platelets adhere to the intima and may secrete platelet-derived extracellular vesicles (pEVs) and communicate with vascular smooth muscle cells (VSMCs). In vitro, pEVs stimulated VSMCs to promote collagen secretion and cell adhesion. MRNA sequencing analysis of a carotid artery intimal injury model showed that ECM factors, including col8a1, col8a2, col12a1, and elastin, were upregulated. Subsequently, ingenuity pathway analysis (IPA) was used to examine the possible signaling pathways involved in the formation of ECM, of which the Akt pathway played a central role. In vitro, pEVs activated Akt signaling through the PIP3 pathway and induced the production of Col8a1. MicroRNA (miR) sequencing of pEVs released from activated platelets revealed that 14 of the top 30 miRs in pEVs targeted PTEN, which could promote the activation of the Akt pathway. Further research showed that the most abundant miR targeting PTEN was miR-92a-3p, which promoted Col8a1 expression. Interestingly, knockdown of Col8a1 expression in vivo abrogated the increase in carotid artery stiffness and simultaneously increased the degree of neointimal hyperplasia. Our results revealed that pEVs may deliver miR-92a-3p to VSMCs to induce the production and secretion of Col8a1 via the PTEN/PIP3/Akt pathway, subsequently increasing vascular stiffness. Therefore, pEVs and key molecules may be potential therapeutic targets for treating neointimal hyperplasia.

α -Lipoic Acid-Plus Ameliorates Endothelial Injury via Inhibiting the Apoptosis Pathway Mediated by Intralysosomal Cathepsins in Vivo and Vitro Endothelial Injury Model

PurposeWe tried to explore the potential role of the α-Lipoic acid-plus (LAP) in endothelial injury in vitro and vivo models. Simultaneously, possible endovascular protective mechanisms of LAP were also investigated further. MethodsIn vitro, oxyhemoglobin (OxyHb) stimulating human umbilical vein endothelial cells (HUVECs) simulated intimal injury. In vivo, carotid artery angioplasty injury was used to generate a model of rat carotid artery intimal injury (CAII). HUVECs and rats were treated with desferrioxamine (DFO) and LAP. ResultsIn experiment 1, we found that the expressions of Cathepsin B/D in endothelial tissue increased and reached peak point in 48 hours post rat CAII. In experiment 2, firstly, the protein levels of Cathepsin B/D, cleaved-caspase-3, Bax, Ferritin, Transferrin Receptor (TfR) markedly increased after CAII and reversed by DFO and LAP treatments. Besides, DFO and LAP treatments also reduced oxidative stress level and endothelial cells (ECs) necrosis of the damaged endometrium. In experiment 3, firstly, the protein levels of Cathepsin B/D, cleaved-caspase-3, Bax, Ferritin and TfR apparently increased post OxyHb stimulation, which were further aggravated by the addition of iron and decreased by DFO and LAP treatments. Moreover, DFO and LAP significantly ameliorated oxidative stress level, HUVECs injury, iron level, mitochondrial damage and were beneficial to maintain lysosomal integrity. Finally, LAP may have exerted more significant endovascular protective effects than DFO.ConclusionsLAP probably exerted endovascular protective effects via inhibiting the apoptosis pathway mediated by intralysosomal Cathepsins by chelating excessive iron in endothelial lysosomes post intimal injury.

Creating an appropriate access for endovascular repair by replacing a dissected femoral artery in aortic dissection

Transfemoral endovascular repair has been widely accepted as an effective treatment for type B aortic dissection. However, if the dissection extends to the femoral artery, the transfemoral approach increases the risk of access complications. We describe a case of acute complicated type B aortic dissection involving the dissected bilateral femoral arteries. Successful endovascular repair without access complications was performed through an appropriate access route created by a femoral arterial conduit. We believe that this approach results in reliable cannulation of the true lumen and the reduction of the risk for intimal injury in aortic dissection with the dissected femoral artery.