Layers Of Vessel Wall Research Articles

Abdominal involvement as a primary manifestation of systemic or isolated gastrointestinal vasculitis

Systemic vasculitides can cause a wide variety of gastrointestinal manifestations (GI) ranging from mild and frequently nonspecific abdominal pains to potentially life-threatening bowel perforations. Vascular involvement in systemic vasculitides can affect any GI blood vessel, most commonly mesenteric, hepatic, or splenic arteries. Inflammatory changes affecting different layers of arterial vessel walls can lead to aneurysmatic dilatation or blood vessel occlusion with subsequent organ ischemia leading to mucosal ulcerations, GI bleeding, perforations, or bowel obstruction. While the presence of extraintestinal manifestations may aid in diagnosis, delays in making appropriate diagnoses and rapid initiation of glucocorticoid and immunosuppressive treatment can have detrimental consequences. Awareness of isolated gastrointestinal vasculitis is of particular importance as it frequently remains undiagnosed until end-stage organ damage becomes apparent. Vasculitis mimics such as vascular Ehlers-Danlos syndrome or fibromuscular dysplasia add another lay of complexity in approaching patients with suspected GI vasculitis and should always be carefully considered.

A histological study of vessel wall reaction after endovenous ultrasound ablation in an animal model

Introduction. Along with the generally accepted thermal methods of saphenous varicose veins ablation, the use of non-thermal and combined methods becomes attractive. Due to the variety of mechanisms of action, low-frequency ultrasound is a promising technology for performing a wide range of minimally invasive intravascular operations, including the treatment of varicose veins. Aim. To elucidate the mechanism of action of a novel endovenous ultrasound ablation method and evaluate its effect on vein wall injury and lumen occlusion in an animal model. Materials and methods. A total of 34 central ear vein (CEV) medial ramus were treated in 17 rabbits according to the follow-up protocol. Six femoral veins from three rabbits enrolled into the acute experiment were harvested 45 min after the procedure. All treated CEV medial ramus in the follow-up experiment were divided into four treatment groups with an observation time of: (0) 30 days, control procedure; (1) 60 days, ultrasound ablation; (2) 95 days, ultrasound ablation; (3) 138 days, ultrasound ablation. Results. Occlusion was achieved in all but one CEV medial ramus (29/30; 97%) treated with ultrasound. Histologic examination of treated veins showed heat- and mechanical-induced changes in the vein wall, such as abrasion of the endothelium and fibrotic lesions in the tunica media and tunica adventitia. The occluded segments consisted mainly of cellular fibrotic material. In the acute group, histological evidence of damage to all vessel wall layers was found. Discussion. Ultrasound ablation results in homogeneous and uniform damage to the venous wall. The results of this study suggest that the ultrasound treatment leads to venous occlusion by the additive thermomechanical mechanism of damage to the vessel wall. Conclusions. Endovenous ultrasound ablation showed a similar pattern of thermal damage as endovenous laser (EVLA) and radiofrequency ablation (RFA) and damage to the endothelium as mechanochemical ablation (MOCA). Four months after ultrasound ablation, the occlusion rate was 90%.

Regulatory T Cells in Atherosclerosis: Is Adoptive Cell Therapy Possible?

Atherosclerosis is an insidious vascular disease with an asymptomatic debut and development over decades. The aetiology and pathogenesis of atherosclerosis are not completely clear. However, chronic inflammation and autoimmune reactions play a significant role in the natural course of atherosclerosis. The pathogenesis of atherosclerosis involves damage to the intima, immune cell recruitment and infiltration of cells such as monocytes/macrophages, neutrophils, and lymphocytes into the inner layer of vessel walls, and the accumulation of lipids, leading to vascular inflammation. The recruited immune cells mainly have a pro-atherogenic effect, whereas CD4+ regulatory T (Treg) cells are another heterogeneous group of cells with opposite functions that suppress the pathogenic immune responses. Present in low numbers in atherosclerotic plaques, Tregs serve a protective role, maintaining immune homeostasis and tolerance by suppressing pro-inflammatory immune cell subsets. Compelling experimental data suggest that various Treg cell-based approaches may be important in the treatment of atherosclerosis. Here we highlight the most recent advances in our understanding of the roles of FOXP3-expressing CD4+ Treg cells in the atherogenic process and discuss potential translational strategies for the treatment of atherosclerosis by Treg manipulation.

MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by muscularized pulmonary blood vessels, leading to right heart hypertrophy and cardiac failure. However, state-of-the-art therapeutics fail to target the ongoing remodeling process. Here, this study shows that matrix metalloproteinases (MMP)-1 and MMP-10 levels are increased in the medial layer of vessel wall, serum, and M1-polarized macrophages from patients with PAH and the lungs of monocrotaline- and hypoxia-induced PAH rodent models. MMP-10 regulates the malignant phenotype of pulmonary artery smooth muscle cells (PASMCs). The overexpression of active MMP-10 promotes PASMC proliferation and migration via upregulation of cyclin D1 and proliferating cell nuclear antigen, suggesting that MMP-10 produced by infiltrating macrophages contributes to vascular remodeling. Furthermore, inhibition of STAT1 inhibits hypoxia-induced MMP-10 but not MMP-1 expression in M1-polarized macrophages from patients with PAH. In conclusion, circulating MMP-10 could be used as a potential targeted therapy for PAH.

Intra-articular leiomyoma of the knee mimicking a ganglion cyst in a child: A case report and review of literature.

Introduction and importanceAngioleiomyoma is a rare benign soft tissue tumor of smooth muscle getting its origin from the muscular layer of vessel walls. The localized type of leiomyoma occurs on the skin, deep soft tissues, in the genitourinary, gastrointestinal, and respiratory tracts.Case presentationWe report a case of a 16-year-old patient who presented with an intra-articular leiomyoma developed in the anterior cruciate ligament and treated with arthroscopy.Clinical discussionAngioleiomyoma can occur anywhere in the body and is most often seen in the extremities, particularly the lower limbs, but is very rare in the knee joint. Angioleiomyoma should be included in the differential diagnosis of nodular lesions mimicking loose body, such as lipomas, inclusion cysts, ganglion, pigmented villonodular synovitis (PVNS), fibroma, nodular synovitis, hemangioma, synovial sarcoma, myopericytoma, leiomyosarcomas, glomus tumor.ConclusionAngioleiomyoma related to the cruciate ligaments of the knee should be considered in the differential diagnosis of a painful knee especially when associated with a decreased of range of motion of knee. The arthroscopic debridement should be considered the treatment of choice in order to reliably restore active ROM.

Bone-forming perivascular cells: Cellular heterogeneity and use for tissue repair.

Mesenchymal progenitor cells are broadly distributed across perivascular niches-an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a, among others. Purified adventicytes (such as CD10+ , CD107alow , and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering.

Surgical perspective in pseudoaneurysm of peripheral arteries: a better limb salvage option

Aneurysm involve all three layers of vessel wall. Psudoaneurysm also known as false aneurysm is a collection of blood that forms between the two outer layers of an artery. Femoral and popliteal artery aneurysms account for more than 90% of peripheral aneurysms, with popliteal artery aneurysms being the most common (70%). The estimated incidence of femoral and popliteal aneurysms is approximately 7/100,000 men and 1/100,000 women. Femoral aneurysms usually involve the common femoral artery but may occasionally extend or be limited to the superficial femoral artery (SFA) in the midthigh. Femoral and popliteal aneurysms are commonly associated with other aneurysms, with approximately 80% of patients having multiple aneurysms. Femoral and popliteal aneurysms show a high incidence of thromboembolic complications, which can result in limb loss. Pseudoaneurysm, if left untreated can result in deadly limb loss.

Microdistribution of Magnetic Resonance Imaging Contrast Agents in Atherosclerotic Plaques Determined by LA-ICP-MS and SR-\u03bcXRF Imaging

PurposeContrast-enhanced magnetic resonance imaging (MRI) has the potential to replace angiographic evaluation of atherosclerosis. While studies have investigated contrast agent (CA) uptake in atherosclerotic plaques, exact CA spatial distribution on a microscale is elusive. The purpose of this study was to investigate the microdistribution of gadolinium (Gd)- and iron (Fe) oxide-based CA in atherosclerotic plaques of New Zealand White rabbits.ProceduresThe study was performed as a post hoc analysis of archived tissue specimens obtained in a previous in vivo MRI study conducted to investigate signal changes induced by very small superparamagnetic iron oxide nanoparticles (VSOP) and Gd-BOPTA. For analytical discrimination from endogenous Fe, VSOP were doped with europium (Eu) resulting in Eu-VSOP. Formalin-fixed arterial specimens were cut into 5-μm serial sections and analyzed by immunohistochemistry (IHC: Movat’s pentachrome, von Kossa, and Alcian blue (pH 1.0) staining, anti-smooth muscle cell actin (anti-SMA), and anti-rabbit macrophage (anti-RAM-11) immunostaining) and elemental microscopy with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and synchrotron radiation μX-ray fluorescence (SR-μXRF) spectroscopy. Elemental distribution maps of Fe, Eu, Gd, sulfur (S), phosphorus (P), and calcium (Ca) were investigated.ResultsIHC characterized atherosclerotic plaque pathomorphology. Elemental microscopy showed S distribution to match the anatomy of arterial vessel wall layers, while P distribution corresponded well with cellular areas. LA-ICP-MS revealed Gd and Fe with a limit of detection of ~ 0.1 nmol/g and ~ 100 nmol/g, respectively. Eu-positive signal identified VSOP presence in the vessel wall and allowed the comparison of Eu-VSOP and endogenous Fe distribution in tissue sections. Extracellular matrix material correlated with Eu signal intensity, Fe concentration, and maximum Gd concentration. Eu-VSOP were confined to endothelium in early lesions but accumulated in cellular areas in advanced plaques. Gd distribution was homogeneous in healthy arteries but inhomogeneous in early and advanced plaques. SR-μXRF scans at 0.5 μm resolution revealed Gd hotspots with increased P and Ca concentrations at the intimomedial interface, and a size distribution ranging from a few micrometers to submicrometers.ConclusionsEu-VSOP and Gd have distinct spatial distributions in atherosclerotic plaques. While Eu-VSOP distribution is more cell-associated and might be used to monitor atherosclerotic plaque progression, Gd distribution indicates arterial calcification and might help in characterizing plaque vulnerability.

Angioleiomyoma presenting as a nodular swelling of leg: Report of a rare painful benign soft tissue tumor

Angioleiomyoma is a slow-growing benign pericytic tumor originating from the tunica media layer of blood vessel wall and represents 4–5% of all benign soft tissue tumors. Vascular leiomyomas show a greater predilection for the lower extremities than other superficial leiomyomas. Excisional biopsy of the tumor is both diagnostic and curative, with a low recurrence rate reported in the literature and excellent prognosis. Malignant transformation is very rare. Whenever a patient presents with a painful mass in the lower extremity, the diagnosis of leiomyoma should be considered. We present a case of a 30-year-old male with angioleiomyoma of left lower leg who presented with painful slow growing nodular swelling since six years. The mass was excised and on microscopic examination a diagnosis of angioleiomyoma was rendered, which was confirmed by positivity for smooth muscle actin on immunohistochemistry. Keywords: Angioleiomyoma, Angiomyoma, Pericytic tumor, SMA, Vascular leiomyoma.

Molecular differences between arterial and venous grafts in the first year after coronary artery bypass grafting.

Despite commonly used for coronary artery bypass surgery, saphenous vein (SV) grafts have significantly lower patency rates in comparison to internal thoracic artery (ITA) grafts, which might be due to the structural characteristics of the vessel wall but also due to differences in oxidative stress adaptation and molecular signaling and regulation. This human post mortem study included a total of 150 human bypass grafts (75 SV grafts and 75 ITA grafts) obtained from 60 patients divided into five groups due to the time period of implantation: group 1: baseline group without grafting; group 2: 1day; group 3: > 1day-1week; group 4: > 1week-1month; group 5: > 1month-1year. Pieces of 3mm length were fixed with formaldehyde, dehydrated, wax embedded, cut into sections of 3µm thickness, and histologically and immunohistochemically examined. Over the whole time period, we observed a lower neointima formation and a better preserved media in ITA grafts with a higher percentage of TNF-α, PDGFR-α, and VEGF-A in nearly all vessel wall layers, a higher amount of MMP-7, MMP-9, EGFR, and bFGF positive cells in SV grafts and a timely different peak not only between ITA and SV grafts but also within the various vessel wall layers of both graft types. Since most of the examined growth factors, growth factor receptors and cytokines are regulated by MAPKs, our results suggest an activation of different pathways in both vessel graft types immediately after bypass grafting.

Abstract B50: Tissue factor-targeting CAR-NK cells for immunotherapy of triple-negative breast cancer

Abstract The objective of the study is to develop tissue factor (TF)-targeted chimeric antigen receptor-natural killer (TF-CAR-NK) cell immunotherapy for the treatment of triple-negative breast cancer (TNBC). TNBC represents nearly 15% of globally diagnosed breast cancer, which is also the most frequently diagnosed cancer in women in the United States. Due to the lack of validated therapeutic target molecules, TNBC is one of the most difficult-to-treat malignancies, and, in most cases, is considered an incurable malignancy. CAR-expressing NK and T-cell therapy represents a novel cancer immunotherapy approach. To address the unmet issue, we first identified that TF is a novel, common, yet selective membrane-bound surface protein receptor and oncotarget for TNBC on the TNBC cancer cells, tumor neovascular endothelial cells and cancer stem cells. It is worth noting that under physiologic conditions, TF is not expressed on normal peripheral lymphocytes such as NK, B, T cells and monocytes, nor on the cells (quiescent vascular endothelial cells) forming the inner layer of normal vasculature, but is solely restricted on some cells (such as pericytes and smooth muscle cells) that are located outside the blood circulation and inner layer of blood vessel walls. Then we developed and tested a novel TF-targeting CAR-NK cell line (NK92MI, a human NK line derived from NK92 after being transfected for endogenous production of interleukin-2) expressing factor VII light chain, natural ligand for TF, as TF-targeting domain followed by CD28-4-1BB-CD3zeta with or without a hinge region of human IgG1 as TF-CAR1 dimer or monomer for CAR-NK immunotherapy of TNBC. Our preclinical results demonstrate that both the TF-CAR1 dimer and monomer-NK cells can kill TNBC cells in vitro and are effective and safe for the treatment of TNBC in mouse models of TNBC cell line-derived and patient’s tumor-derived xenografts (CDX and PDX). Thus, this study established the proof of concept of targeting TF for CAR-NK immunotherapy of TNBC and may warrant further investigation for TNBC patients. Accumulating evidence suggested that TF is selectively expressed in pathologic angiogenesis-dependent as well as macrophage-associated human diseases. Pathologic angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer (including solid cancer, acute leukemia and sarcoma), age-related macular degeneration, endometriosis and rheumatoid arthritis, whereas macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (HIV and Ebola). If successful, TF-CAR immunotherapy may have potential to treat a broad range of angiogenesis-dependent or macrophage-associated human diseases. Acknowledgments: This work was supported by the Dr. Ralph and Marian Falk Medical Research Trust Awards Programs and partly by an NCI grant (R21CA216697). Z.H. is the inventor of PCT/U.S. Pending Patents on “Tissue Factor-Targeting CAR-NK and CAR-T Cell Therapy.” Citation Format: Zhiwei Hu. Tissue factor-targeting CAR-NK cells for immunotherapy of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B50.

Understanding how defects in familial thoracic aneurysm and dissection (FTAAD)‐associated mutations in MAGP2 (MFAP5) affect its extracellular matrix localization and regulation of TGF‐β/SMAD signaling

In familial thoracic aneurysm and dissection (FTAAD), the aorta becomes weakened, stretching the vessel, a process known as aortic dilation, which in extreme cases can lead to tearing of the vessel wall layers, commonly referred to as aortic dissection. The direct consequences of FTAAD are stroke or heart attack that can potentially result in death of the patient. Research on Marfan Syndrome (MFS) and Loeys‐Dietz Syndrome (LDS) have shown that genes associated with similar aortic abnormalities have alterations in the TGF‐β/SMAD signaling pathway as well as extracellular matrix proteins (Faivre et al., 2007, Mizuguchi et al., 2004, and Loeys et al., 2006). Mutations in MFAP5, a gene that encodes for microfibril‐associated glycoprotein 2 (MAGP2), have been found in two FTAAD families, a nonsense mutation R158* and a missense mutation W21L (Barbier et al., 2014). The current working hypothesis is that MAGP2 normally plays an inhibitory role in TGF‐β/SMAD signaling, and that the FTAAD‐associated mutations are loss of function, since aortic tissue from a patient with the W21L mutation showed high phospho‐SMAD (p‐SMAD) levels. Moreover, MAGP2 has been shown to directly bind to active TGF‐β1 in vitro (Combs et al., 2013), and we have confirmed the results of Barbier et al. that the R158* mutant is poorly secreted. In contrast, the defect in the W21L mutant protein remains unidentified. It was secreted and bound to extracellular fibrillin microfibrils similar to wild‐type MAGP2 in our cell culture studies. What remains untested is whether FTAAD‐associated MAGP2 mutant proteins directly or indirectly affect TGF‐β/SMAD signaling. Therefore, the objective of this study is to determine whether R158* MAGP2 and W21L MAGP2 mutant proteins lose the ability to regulate TGF‐β signaling, leading to an increase in p‐SMAD2/3 levels in the cell. A TGF‐β signaling assay will be used to test soluble MAGP2 proteins, and fluorescent western blotting will then quantify the level of p‐SMAD 2/3 in whole cell lysate of MG63 cells, which expresses the TGF‐β receptor. Verification of both p‐SMAD2/3 and total SMAD antibodies have been completed via standard chemiluminescent protocols, and are currently being optimized for fluorescent detection. In parallel, stable cell lines are being produced to express wild‐type, R158*, or W21L MAGP2. A cell line expressing wild‐type MAGP2 has been generated, and the other two cell lines are being checked via immunofluorescence and western blotting to confirm that the cell lines express MAGP2. An understanding of how MAGP2 regulates the TGF‐β signaling could lead to the engineering of drugs to target mutant MAGP2 in hopes of improving the outcomes of FTAAD.Support or Funding InformationThis work was supported by the Department of Biological Science research funds (A. Miyamoto), CIRM Bridges to Stem Cell Research (A. Burcham, A. Keith), and HHMI (R. Daniels).

Abstract WP1: High-Frequency Optical Coherence Tomography for Cerebrovascular Disease

Introduction: Optical coherence tomography (OCT) has played an important role in the diagnosis and treatment guidance in coronary artery disease. However, existing OCT systems are not suitable for routine neurovascular applications due to the size and tortuosity of the arteries. Hypothesis: We seek to demonstrate a prototype high-frequency OCT (HF-OCT) capable of high-resolution imaging in simulated cerebrovascular anatomy. Methods: A low-profile HF-OCT system was constructed with an image resolution approaching 10μm. Using an in vitro, patient-specific model of the circle of Willis with circulating porcine blood, we characterized the delivery of the device and ability to image in a tortuous path. Also, human cadaver intracranial atherosclerosis plaques were imaged with HF-OCT and assessed by an expert imager. Finally, neurovascular devices were implanted in 8 pigs (Fig 1) and HF-OCT imaging was compared with gold-standard DSA and CT. Results: In the phantom, optimal blood clearance was achieved through an intermediate catheter (5 Fr Navien) with infusion of contrast at 5 ml/s in the internal carotid and basilar artery, and 3 ml/sec in the MCA. The in vivo study demonstrated that both malapposition of devices or thrombus formation along the device surface could be reliably diagnosed among 3 reviewers (Fleiss’s kappa of 0.87 and 0.9, respectively). This agreement was superior to DSA and CT. Imaging in tortuous swine brachial showed in all cases imaging free of artifacts, uniform illumination and ability to visualize vessel wall layers. Plaque types including ‘lipid pools’, fibrotic, and calcific tissue from cadaver specimens of ICAD could be adequately depicted by HF-OCT. Conclusion: In vitro, in vivo and ex vivo characterization of a novel HF-OCT device has shown it is capable of imaging in the tortuous intracranial vascular anatomy. This technology has to potential to aid in the diagnosis of cerebrovascular disease and guide optimal endovascular treatment.

Follicular regulatory T cell in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease involving the infiltration of immune cells, such as monocytes/macrophages, neutrophils, T cells, and B cells, into the inner layer of vessel walls. T and B cell functions in the process of atherogenesis, as well as their mutual regulation, have been investigated but several aspects remain to be clarified. In the present review, we give a brief overview of the functions of follicular regulatory T cell (Tfr) on follicular T (Tfh) and B cell regulation related to atherosclerosis pathogenesis, including their influence on lymphangiogenesis and lipoprotein metabolism. We will also discuss their potential therapeutics properties in the resolution of established atherosclerotic lesions.

A Survey on Coronary Atherosclerotic Plaque Tissue Characterization in Intravascular Optical Coherence Tomography.

Atherosclerotic plaque deposition within the coronary vessel wall leads to arterial stenosis and severe catastrophic events over time. Identification of these atherosclerotic plaque components is essential to pre-estimate the risk of cardiovascular disease (CVD) and stratify them as a high or low risk. The characterization and quantification of coronary plaque components are not only vital but also a challenging task which can be possible using high-resolution imaging techniques. Atherosclerotic plaque components such as thin cap fibroatheroma (TCFA), fibrous cap, macrophage infiltration, large necrotic core, and thrombus are the microstructural plaque components that can be detected with only high-resolution imaging modalities such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Light-based OCT provides better visualization of plaque tissue layers of coronary vessel walls as compared to IVUS. Three dominant paradigms have been identified to characterize atherosclerotic plaque components based on optical attenuation coefficients, machine learning algorithms, and deep learning techniques. This review (condensation of 126 papers after downloading 150 articles) presents a detailed comparison among various methodologies utilized for plaque tissue characterization, classification, and arterial measurements in OCT. Furthermore, this review presents the different ways to predict and stratify the risk associated with the CVD based on plaque characterization and measurements in OCT. Moreover, this review discovers three different paradigms for plaque characterization and their pros and cons. Among all of the techniques, a combination of machine learning and deep learning techniques is a best possible solution that provides improved OCT-based risk stratification.

Non-pharmacological modification of endothelial function: An important lesson for clinical practice

During the last few generations a rapid increase in the prevalence of cardiovascular diseases has been observed. This epidemiologic fact is in a wide range due to endothelial dysfunction. Endothelium, the inner layer of vessel wall, is a crucial structure in the proper functioning of the cardiovascular system. Next to classic cardiovascular risk factors such as diabetes, obesity, atherosclerosis and hypertension, endothelial dysfunction has become understood as one of the most important elements of cardiovascular pathologies, ranging from ischemic heart disease, stroke to carcinogenesis. This has given rise to a crucial need to develop new therapeutic directions aimed at ameliorating the endothelial function. A healthy lifestyle and proper well-balanced diet seem to be even more important than pharmacotherapy. Therefore, non-pharmacological interventions have become bullet points in a list of endothelial-targeted treatment strategies. Currently, several compounds have been studied as candidates for endothelial function improvement. L-arginine supplementation is proved to reduce fat content. It also preferably modifies carbohydrates metabolism and the expression of genes responsible for increased cardiovascular risk. Spirulina increases the expression of endothelial nitric oxide synthase, which ameliorates nitrogen oxide production and leads to a decrease in blood pressure. The beneficial effect of green tea catechins is based mainly on the inactivation of reactive oxygen. Allicin present in garlic shows both antioxidative and anti-inflammatory effects. Probiotics prevent endothelial dysfunction in effect of improved vascular oxidative stress. Physical activity also demonstrates a number of mechanisms that ameliorate endothelial function. The impact of endothelial function in the complex pathology of cardiovascular diseases reflects a number of scientific proofs showing favorable effects of non-pharmacological interventions in endothelial dysfunction treatment.

Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis-Dependent as Well as Macrophage-Associated Human Diseases.

Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases.

The effects of membrane cholesterol on the mechanics of vascular smooth muscle cell

As the major cellular component of blood vessel wall, vascular smooth muscle cell (VSMC) plays important roles at each stage of atherosclerosis by proliferation and migration toward the inner layer of blood vessel wall. It is also known that cholesterol is not only the major factor involved in fatty deposition in the atherosclerotic lesion, but also plays an important role as a regulator of cell mechanics, spreading, and migration. A further complication is the mechanical environment of the vascular wall, which undergoes progressive stiffening with aging and hypertension and thus accelerates development of atherosclerosis. Therefore, it is important to investigate the combined effect of cholesterol and mechanical environment on VSMC and determine how it alters VSMC functional characteristics such as cell stiffness and adhesion. VSMCs used in this study were enzymatically isolated from the descending aorta of male Sprague‐Dawley rats and cultured in DMEM with 10% FBS in a humidified incubator at 37°C and 5% CO2. Cell adhesion was measured for 50–70% confluent cells with an atomic force microscope (AFM) system and the fibronectin (FN) or N‐cadherin coated stylus AFM probes at 100 nm/sec retraction speed. Cell stiffness was tested with spherical AFM probe (5μm diameter) at 1 μm/sec indentation speed. Cells were treated with 5mM Methyl‐β‐cyclodextrin for 1 h for cholesterol depletion prior to the AFM experiment. Our results showed that cholesterol depletion significantly increased N‐cadherin mediated cell adhesion by ~20% and adhesion probability by ~35%, respectively. While α5β1/FN adhesion force significantly decreased upon membrane cholesterol depletion. Moreover, our results suggested that cholesterol depletion significantly reduced VSMCs stiffness by 47% compared to control cells. All together, these results reveal that membrane cholesterol is a key regulator for cellular stiffness and integrin/cadherin‐mediated cell adhesion. The knowledge that we obtained in this project may lead to a novel therapeutic strategy that could potentially control and block VSMC migration and prevent the formation of atherosclerotic plaque by regulating integrin and/or cadherin mediated cell adhesion.Support or Funding Information15SDG25420001 (AHA)

Spontaneous Arterial Dissection—Risk Factors And Clinical Features: Study Of 70 Cases And Review Of Literature

Dissection refers to a serious condition that begin as a tear or rupture in the inner layers of large vessel wall. Tear allows the blood to surges through the layers, leads to intramural hematoma or an aneurysmal dilatation, either of which can be a source of thromboembolism. Ischemic symptoms in surrounding structures are more often secondary to embolism. Dissections are labeled spontaneous in the absence of major blunt or penetrating trauma. The incidence rates for spontaneous carotid artery dissection have been reported to be 2.5 to 3 per 100,000 population. The average annual incidence for vertebral artery dissection were calculated to be 1 to 1.5 per 100,000. Typical clinical features seen with dissection include unilateral headache, ipsilateral Homer's syndrome, oculosympathetic palsy, prominent neck and facial pain, retinal ischemia, and symptoms of focal brain ischemia due to the site of dissection. The reason of dissection occurrence is still unknown but numerous factors e.g. connective tissue disorders, hyperhomocystinemia, fibromuscular dysplasia, recent infection, etc. may underlie spontaneous or minor trauma dissections. Patients with Spontaneous dissection are more susceptible to developing to stroke and its morbidity and mortality. In this retrospective study, we evaluate the clinical features, risk factors, treatment and outcome of spontaneous dissection in 70 patients (31 female and 39 male), referred to Namazi hospital between September 2012 and September 2016. The diagnosis of arterial dissection was established by qualified physicians according to radiological and clinical features. Patients with traumatic dissection and a history of major or minor head and neck injury were excluded. Subjects were observed for multiple risk factors such as age dependent risk factors, family history of venous thrombosis, history of trauma, coagulopathies, infectious diseases, systemic disorders, arterio-venous malformations and autoimmune diseases. We also investigated for any history of OCP administration in female patients. The collected data was evaluated using SPSS 16. Chi-square test were performed for the comparison of qualitative variables. And p<0.05 was considered as the level of significance in two-tailed tests. Statistical analysis of our data found a significant correlation between hypertension and occurrence of spontaneous arterial dissection. The findings confirm that hypertension, OCP administration and smoking can increase the risk of CVST significantly.

Donor-Specific Antibodies Are Produced Locally in Ectopic Lymphoid Structures in Cardiac Allografts.

Cardiac allograft vasculopathy (CAV) is a transplant pathology, limiting graft survival after heart transplantation. CAV arteries are surrounded by ectopic lymphoid structures (ELS) containing B cells and plasma cells. The aim of this study was to characterize the antigenic targets of antibodies produced in ELS. Coronary arteries and surrounding epicardial tissue from 56 transplant recipients were collected during autopsy. Immunofluorescence was used to identify antibody-producing plasma cells. Immunoglobulin levels in tissue lysates were measured by enzyme-linked immunosorbent assay and analyzed for donor-specific HLA antibodies by Luminex assay. Cytokine and receptor expression levels were quantified using quantitative polymerase chain reaction. Plasma cells in ELS were polyclonal and produced IgG and/or IgM antibodies. In epicardial tissue, IgG (p < 0.05) and IgM levels were higher in transplant patients with larger ELS than smaller ELS. In 4 of 21 (19%) patients with ELS, donor-specific HLA type II antibodies were detected locally. Cytokine and receptor expression (CXCR3, interferon γ and TGF-β) was higher in large ELS in the epicardial tissue than in other vessel wall layers, suggesting active recruitment and proliferation of T and B lymphocytes. ELS exhibited active plasma cells producing locally manufactured antibodies that, in some cases, were directed against the donor HLA, potentially mediating rejection with major consequences for the graft.