Loss Of Smooth Muscle Cells Research Articles

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.

Cathepsin K Deficiency Reduces Elastase Perfusion–Induced Abdominal Aortic Aneurysms in Mice

Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4(+) T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3(+) macrophage accumulation or CD31(+) microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4(+) T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.

Persistent Inflammation Leads to Proliferative Neoplasia and Loss of Smooth Muscle Cells in a Prostate Tumor Model

In prostate cancers, epidemiological data suggest a link between prostate inflammation and subsequent cancer development, but proof for this concept in a tumor model is lacking. A constitutively active version of IκB kinase 2 (IKK2), which is activated by many inflammatory stimuli, was expressed specifically in the prostate epithelium. Constitutive activation of the IKK2/nuclear factor κB axis was insufficient for prostate transformation. However, in combination with heterozygous loss of phosphatase and tensin homolog, IKK2 activation led to an increase in tumor size, formation of cribriform structures, and increase in fiber in the fibroblastic stroma. This phenotype was coupled with persistent inflammation evoked by chemokine expression in the epithelium and stroma. The hyperplastic and dysplastic epithelia correlated with changes evoked by decreased androgen receptor activation. Conversely, inflammation correlated with stromal changes highlighted by loss of smooth muscle cells around prostate ducts. Despite the loss of the smooth muscle barrier, tumors were rarely invasive in a C57BL/6 background. Data mining revealed that smooth muscle markers are also downregulated in human prostate cancers, and loss of these markers in primary tumors is associated with subsequent metastasis. In conclusion, our data show that loss of smooth muscle and invasiveness of the tumor are not coupled in our model, with inflammation leading to increased tumor size and a dedifferentiated stroma.

Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice

Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer’s disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood–brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice.

Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD)

Esophageal symptoms in mixed connective tissue disease (MCTD) have been investigated radiologically. We investigated the esophageal lesions in MCTD histopathologically, and analyzed relationships between these lesions and autoantibodies extracted from the serum of MCTD patients. Esophageal tissues from 27 MCTD patients submitted to autopsy were examined. We compared histopathological features of the esophagus in different wall layers from the mucosa, submucosa, and muscular layer to the adventitia, and in the upper, middle, and lower portions of esophagus. The most striking change observed was severe atrophy and occasional loss of smooth muscle cells in the muscular layer, followed by fibrosis. These muscular changes were particularly prominent in the inner layer of the lower esophagus. Immunohistochemically, degenerated muscular tissues of the esophagus were positive for anti-IgG and anti-C3 antibodies, but not for anti-IgM antibodies. IgG fractions extracted from three MCTD patients were immunohistochemically used to examine whether some antibodies in MCTD patients showed reactivity for esophageal components. The IgG fractions isolated from MCTD patients reacted with smooth muscle from non-connective tissue disease cases, suggesting that some serum antibodies may trigger esophageal changes. These findings suggest that esophageal lesions associated with clinical dysphagia in MCTD may be related to autoantibodies.

Interleukin‐2 is present in human blood vessels and released in biologically active form by heparanase

Interleukin-2 is a multifaceted cytokine with both immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2 dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2 deficient mice were normal. The aortas of IL-2 deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems.

A link between smooth muscle cell death and extracellular matrix degradation during vascular atrophy

High blood flow induces neointimal atrophy in polytetrafluoroethylene (PTFE) aortoiliac grafts and a tight external PTFE wrap of the iliac artery induces medial atrophy. In both nonhuman primate models, atrophy with loss of smooth muscle cells and extracellular matrix (ECM) begins at ≤4 days. We hypothesized that matrix loss would be linked to cell death, but the factors and mechanisms involved are not known. The purpose of this study was to determine commonly regulated genes in these two models, which we hypothesized would be a small set of genes that might be key regulators of vascular atrophy. DNA microarray analysis (Sentrix Human Ref 8; Illumina, San Diego, Calif; ∼23,000 genes) was performed on arterial tissue from the wrap model (n = 9) and graft neointima from the graft model (n = 5) 1 day after wrapping or the switch to high flow, respectively. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was also performed. Expression of this vascular atrophy gene set was also studied after Fas ligand-induced cell death in cultured smooth muscle cells and organ cultured arteries. Microarray analysis showed 15 genes were regulated in the same direction in both atrophy models: 9 upregulated and 6 downregulated. Seven of nine upregulated genes were confirmed by qRT-PCR in both models. Upregulated genes included the ECM-degrading enzymes ADAMTS4, tissue plasminogen activator (PLAT), and hyaluronidase 2; possible growth regulatory factors, including chromosome 8 open reading frame 4 and leucine-rich repeat family containing 8; a differentiation regulatory factor (musculoskeletal embryonic nuclear protein 1); a dead cell removal factor (ficolin 3); and a prostaglandin transporter (solute carrier organic anion transporter family member 2A1). Five downregulated genes were confirmed but only in one or the other model. Of the seven upregulated genes, ADAMTS4, PLAT, hyaluronidase 2, solute carrier organic anion transporter family member 2A1, leucine-rich repeat family containing 8, and chromosome 8 open reading frame 4 were also upregulated in vitro in cultured smooth muscle cells or cultured iliac artery by treatment with FasL, which causes cell death. However, blockade of caspase activity with Z-VAD inhibited FasL-mediated cell death, but not gene induction. Seven gene products were upregulated in two distinctly different in vivo nonhuman primate vascular atrophy models. Induction of cell death by FasL in vitro induced six of these genes, including the ECM-degrading factors ADAMTS4, hyaluronidase 2, and PLAT, suggesting a mechanism by which the program of tissue atrophy coordinately removes extracellular matrix as cells die. These genes may be key regulators of vascular atrophy.

What Is New in Dilatation of the Ascending Aorta?

A 61-year-old woman presented with atypical chest complaints. Her sister and brother suffered from type A aortic dissection at 47 and 39 years of age, respectively.1 The diameter of the ascending aorta was 4.6 cm as measured with magnetic resonance imaging (Figure 1). Figure 1. Magnetic resonance angiography of the ascending aorta. The diameter at the level of the ascending aorta measures 4.6 cm. The diameter of the aortic root is normal. Acute dissection of the ascending aorta is often lethal. Even when emergency surgery can be performed, associated morbidity and mortality are high. To prevent dissection of the aorta, timely operation on a patient with a known dilatation of the ascending aorta (for normal values, see Table 1) is advised, along with other supportive measures. The guideline for the management of aortic dissection published by the European Society of Cardiology (ESC) task force in 20012 recommends the following for the prevention of aortic dissection in inherited diseases (Marfan syndrome [MFS], Ehlers-Danlos syndrome, annuloaortic ectasia): lifelong β-adrenergic blockade (Class IB), moderate restriction of physical activity (Class IC), periodic routine imaging of the aorta (Class IC), prophylactic replacement of the aortic root before diameter exceeds 5.5 cm (Class 2A), and prophylactic replacement of the aortic root before diameter exceeds 5.0 cm in patients with a family history of dissection (Class 2A). These ESC recommendations received endorsement by the American College of Cardiology (ACC) in 2001. In recent years, insights into the diagnosis and management of these patients have changed. The purpose of the present article is to summarize these changes, referring to this recent case presented at our clinic. View this table: Table 1. Normal Ascending Aortic Dimensions in Adults In patients with aortic dilatation, the aortic wall can be weakened by cystic media degeneration. The media displays loss of smooth muscle cells and fragmentation …

Increased Vascular Injury Reduces the Degree of Intimal Hyperplasia following Angioplasty in Rabbits

Background/Aims: Formation of intimal hyperplasia following angioplastic procedures can lead to complications, including restenosis and accelerated atherosclerosis. The vessel wall media is a main source of neointimal cells. However, evidence suggests that there are additional cell sources, such as the adventitia. Here we investigate whether an extensive loss of vascular smooth muscle cells (VSMCs) in the media results in less intimal hyperplasia or if there is compensatory cell recruitment from the adventitia. Methods:A balloon catheter was pulled through the rabbit carotid artery 4 times (major injury) or 2 times (minor injury). Adventitial cells were labeled with 5-bromo-2-deoxyuridine or PKH26. Results:The major injury, but not the minor injury, resulted in a complete loss of VSMCs in large parts of the media and significant leukocyte infiltration. The major injury resulted in less neointima compared with the minor injury. The thinnest neointima was seen at the most injured parts of the media in the major injury group. Cell-tracking experiments showed that the media, but not the adventitia, served as a source of neointimal cells. Conclusion: An augmented angioplastic injury with extensive VSMC loss in rabbits reduced the degree of intimal hyperplasia. No compensatory recruitment of neointimal cells from the adventitia occurred.

Early innate immune events induced by prolonged cold ischemia exacerbate allograft vasculopathy

BackgroundIschemia/reperfusion induced innate immune injury is inescapable in solid organ transplantation. Prolonged cold ischemia exacerbates the primary manifestation of late graft rejection, allograft vasculopathy (AV). The relationship between prolonged cold ischemia and late graft events is unclear and the subject of this study.MethodsAortic interposition transplants were performed between fully disparate mice treated with CyclosporineA. Allografts were exposed to 20 min or 60 min of cold ischemia and harvested between 1 d-6 wk. Lesion size, smooth muscle cells (SMC), neutrophils (N∅), and CD8+ T cells were quantified.ResultsEarly SMC loss was identical in both groups. When compared to 20 min cold ischemia, grafts exposed to 60 min exhibited greater early N∅ influx, greater SMC proliferation but fewer medial SMC at 1 wk and 2 wk. Subsequently, earlier and greater CD8+ T cell infiltration were seen in the 60 min group with larger lesions at every time point.ConclusionsThese data suggest that the larger neointimal lesions in grafts exposed to 60 min cold ischemia result from enhanced early innate immune events resulting in impaired SMC recovery and subsequent increased adaptive immune response.

Role of diagnostic laparoscopy in assessing resectability of pancreatic and periampullary cancer

Abstracts / International Journal of Surgery 9 (2011) 363–369 368s / International Journal of Surgery 9 (2011) 363–369 368 ROLE OF DIAGNOSTIC LAPAROSCOPY IN ASSESSING RESECTABILITY OF PANCREATIC AND PERIAMPULLARY CANCER Amun Kalia, K.S. Gurusamy, V. Allen, B.R. Davidson. Department of Surgery, Royal Free Campus UCL Medical School, 9 Floor Royal Free Hospital, Pond Street, London. NW3 2QG Background: Surgical resection is the only curative treatment for pancreatic and periampullary cancer. A significant proportion of patients undergo unnecessary laparotomy because of understaging of these tumours. There has been no systematic review or meta-analysis assessing the role of diagnostic laparoscopy in assessing resectability (with curative intent) of pancreatic and periampullary cancer. Methods: A systematic review of studies was performed. Medline, Embase, Cochrane trials register, and Science Citation Index were searched until November 2009. Two reviewers independently identified studies and extracted data. The gold standard was histological confirmation of metastases. Quality of studies was assessed by the QUADAS tool. Metaanalysis was performed using hierarchical summary operating characteristics curve method of combining studies of diagnostic accuracy. Results: 23 studies including a total of 2973 patients were included in the meta-analysis. Most of the patients included in the studies had undergone a staging computerized tomogram (CT scan). Most of the studies performed histological confirmation of metastases before declaring that diagnostic laparoscopy was positive. Most of the studies had low risk of bias in the important aspects of methodological quality. The summary sensitivity and specificity obtained bymeta-analysis were 0.726 and 0.999, corresponding to a post-test probability of 1.00 for a positive diagnostic laparoscopy and 0.14 for a negative diagnostic laparoscopy compared to a baseline probability of 0.36. Thus diagnostic laparoscopy can decrease the probability of unresectable cancer found on laparotomy from 36% to 14%. Conclusions: Routine diagnostic laparoscopy prior to laparotomy can decrease unnecessary laparotomies. PATHOGENESIS OF CYSTIC MEDIAL DEGENERATION IN IDIOPATHIC DILATION OF THE ASCENDING AORTA A.K. Kar , S.K. Nair , M.J. Goddard . University of Cambridge, School of Clinical Medicine, Papworth Hospital, Cambridge CB3 8RE, UK; Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge CB3 8RE, UK; Histopathology, Papworth Hospital, Cambridge CB3 8RE, UK Introduction: Although there have been advances in the surgical management for idiopathic dilation of the ascending aorta, the pathogenesis is still poorly understood. We investigated the histopathological features of cystic medial necrosis or degeneration (CMD). Methods: Tissue samples from sixty patients who underwent surgery for idiopathic dilation of the ascending aorta were fixed and stained so that histopathological features of CMN could be studied using a Leica DMLB microscope. We measured quantitatively loss of medial vascular smooth muscle cells and graded the fragmentation of elastic fibres, accumulation of mucopolysaccarides and elastocalcinosis of the media. Dividing the media into inner and outer segments, we considered regional differences in the aortic wall. Results: HE Welsh Institute of Minimal Access Technology Aims: Surgical simulation is of increasing importance with the advent of working time directives and may eventually fill the gaps in surgical education that have been created. We assessed the feasibility of establishing construct validity in a novel animal tissue model for laparoscopic right hemicolectomy. Materials and Methods: Participants performed two defined sections of a laparoscopic right hemicolectomy using the model developed. The procedures were marked independently by video using the L-CAT Objective Structured Assessment of Technical Skills (OSATS). Participants scores in all domains were compared to the number of real-world lead laparoscopic operator procedures they had performed. Results: Six participants completed a total of 16 procedures. Laparoscopic experience showed a statistically significant positive correlation with performance during the exposure (p1⁄40.005) and vascular pedicle (p1⁄40.05) sections, and the total time taken to complete the task (p1⁄4<0.001). Laparoscopic experience also correlated significantly and positively with technical skill (p1⁄40.02) and less errors (p1⁄40.04). A strong positive correlation was seen in all other measures. Conclusions: This study was able to distinguish surgeons based on their real-world laparoscopic experience using a novel animal tissue right hemicolectomymodel as assessed by OSATS. Thus, the construct validity of the platform is established in this feasibility study. Animal tissue models

IFPA Gabor Than Award lecture: Transformation of the spiral arteries in human pregnancy: Key events in the remodelling timeline

During human pregnancy, the uterine spiral arteries are progressively remodelled to form dilated conduits lacking maternal vasomotor control. This phenomenon ensures that a constant supply of blood is delivered to the materno-fetal interface at an optimal velocity for nutrient exchange. Conversion of a tonic maternal arteriole composed of multiple layers of vascular smooth muscle, elastin and numerous other extracellular matrix components, into a highly dilated yet durable vessel, requires tight regulatory control and the coordinated actions of multiple cell types. Initial disruption of the vascular wall, characterised by foci of endothelial cell loss, and separation and misalignment of vascular smooth muscle cells (VSMC), is coincident with an influx of uterine natural killer (uNK) cells and macrophages. uNK cells are a source of angiogenic growth factors and matrix degrading proteases, thus they possess the capacity to initiate changes in VSMC phenotype and instigate extracellular matrix catabolism. However, complete vascular cell loss, mediated in part by apoptosis and dedifferentiation, is only achieved following colonisation of the arteries by extravillous trophoblast (EVT). EVT produce a variety of chemokines, cytokines and matrix degrading proteases, enabling them to influence the fate of other cells within the placental bed and complete the remodelling process. The complex interplay of cell–cell and cell–matrix interactions required for effective vascular transformation will be examined, with a particular focus on the role of (i) uNK cells and (ii) the enzyme matrix metalloproteinase-12 (MMP-12). Parallels with remodelling events occurring in other vascular beds will also be drawn.

A shear stress responsive gene product PP1201 protects against Fas-mediated apoptosis by reducing Fas expression on the cell surface

Cells that form vascular system employ different mechanisms to offset deleterious consequences of exposure to cytokines and cells present in blood. Vascular homeostasis is sustained in part by genes, whose expression increases in response to hemodynamic forces in these cells. PP1201 (also known as RECS1) is one such gene whose expression level increases in response to laminar shear stress. Aged mice deficient in PP1201 are prone to develop cystic medial degeneration (CMD), a form of aortic aneurism manifested with loss of smooth muscle cells and accumulation of basophilic substances. Here we found that higher levels of PP1201 can protect against Fas ligand (FasL)-induced apoptosis. PP1201 interacted with the Fas receptor (CD95/Apo1) and colocalized with it in the Golgi compartment. Unlike its homolog lifeguard (LFG), PP1201 overexpression in several types of cells including primary human aortic smooth muscle cells (AoSMC) decreased the expression of Fas on the plasma membrane without changing the total Fas levels. Only high but not constitutive level of PP1201 controls Fas signaling. Our data suggest that PP1201 functions as an anti-apoptotic protein and its increased expression in vascular cells can contribute to homeostasis by reducing Fas trafficking to the cell membrane.

Altered Oxidative Stress Responses and Increased Type I Collagen Expression in Bicuspid Aortic Valve Patients

The mechanisms governing extracellular matrix degradation and smooth muscle cell (SMC) loss in the ascending aorta of bicuspid aortic valve (BAV) patients are unknown. We recently reported that expression and induction of metallothionein, a reactive oxygen species scavenger, is reduced in BAV ascending aortic aneurysms relative to nonaneurysmal patients. Tissue and primary SMCs from patients with and without thoracic aortic aneurysms and metallothionein-null and wild-type mice were analyzed for cell viability, vascular endothelial growth factor (VEGF), and type I collagen gene expression during exposure to reactive oxygen species. The BAV SMCs and metallothionein -/- mice failed to induce VEGF under conditions of oxidative stress in vitro. Exogenous VEGF restored resistance to oxidative stress in BAV SMCs to normal. Type I collagen gene induction was increased in BAV aorta. Lack of VEGF induction during exposure to reactive oxygen species suggest that the oxidative stress response is faulty upstream of metallothionein and VEGF in BAV SMCs. Improvement of cell viability with VEGF treatment suggests that the deficient pathway can be rescued by VEGF. Increased type I collagen in BAV suggests that lack of metallothionein/VEGF activation in response to reactive oxygen species may play a role in extracellular matrix homeostasis of the ascending aorta. These data continue to support our hypothesis that BAV SMCs lack sufficient resistance to reactive oxygen species to maintain extracellular matrix homeostasis, which imparts a predisposition to thoracic aortic aneurysms.

Pentoxifylline Promotes Recovery of Erectile Function in a Rat Model of Postprostatectomy Erectile Dysfunction

BackgroundCavernous nerve (CN) injury during radical prostatectomy (RP) causes CN degeneration and secondary penile fibrosis and smooth muscle cell (SMC) apoptosis. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that further inhibits multiple cytokine pathways involved in nerve degeneration, apoptosis, and fibrosis. ObjectivesTo evaluate whether PTX enhances erectile function in a rat model of CN injury. Design, Setting and InterventionsForty male Sprague-Dawley rats underwent CN crush injury and were randomized to oral gavage feeding of phosphate-buffered saline (vehicle) or PTX 25, PTX 50, or PTX 100mg/kg per day. Ten animals underwent sham surgery and received vehicle treatment. Treatment continued for 28 d, followed by a wash-out period of 72h. An additional eight rats underwent resection of the major pelvic ganglion (MPG) for tissue culture and examination of direct effects of PTX on neurite sprouting. MeasurementsIntracavernous pressure recording on CN electrostimulation, immunohistologic examination of the penis and the CN distal to the injury site, and length of neurite sprouts in MPG culture. ResultsDaily oral gavage feeding of PTX resulted in significant improvement of erectile function compared to vehicle treatment in all treated groups. After treatment with PTX 50 and PTX 100mg/kg per day, the expression of neuronal nitric oxide synthase in the dorsal penile nerve was significantly higher than in vehicle-treated rats. Furthermore, PTX treatment prevented collagen deposition and SMC loss in the corpus cavernosum. In the CN, signs of Wallerian degeneration were ameliorated by PTX treatment. MPG culture in medium containing PTX resulted in a significant increase of neurite length. ConclusionsPTX treatment following CN injury in rats improved erectile recovery, enhanced nerve regeneration, and preserved the corpus cavernosum microarchitecture. The clinical availability of this compound merits application in penile rehabilitation studies following RP in the near future.

CADASIL

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited form of small vessel disease, characterized by frequent migraine attacks with aura, recurrent strokes and progressive white matter degeneration. Early vascular cognitive impairment progresses into frank dementia of subcortical type later in life. Linked to mutations in the NOTCH3 gene, CADASIL vasculopathy is associated with accumulation of granular osmiophilic material and NOTCH3 extracellular domain around small caliber arteries and arterioles, and eventual loss of vascular smooth muscle cells. Cerebral blood flow dysregulation has been hypothesized as a major mechanism, largely based on evidence from hemodynamic studies in CADASIL patients. Although animal models expressing CADASIL mutations reproduced the pathology and cerebrovascular dysfunction, the phenotypic spectrum has been quite heterogeneous, possibly due to the choice of genetic constructs and obvious species differences between mouse and man. Nevertheless, these experimental models provide new opportunities to explore the molecular and physiological mechanisms of CADASIL, and address the fundamental question of whether CADASIL phenotype represents loss of NOTCH3 function or gain of a novel and pathological function. Here, I provide an overview of existing animal models of CADASIL and the pathophysiological insights gained from these models.

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients with Thoracic Aortic Disease

TABLE OF CONTENTSPreamble ……………………………….280 Introduction ………………………281 1.1. Methodology and Evidence Review … . .2811.2. Organization of the Writing Committee …2831.3. Document Review and Approval …… .2831.4. Scope of the Guideline ……………283 1.4.1. Critical Issues …………… . .2831.5. Glossary of Terms and

Vascular-Leukocyte Interactions: Mechanisms of Human Decidual Spiral Artery Remodeling in Vitro

Transformation of uterine spiral arteries is critical for healthy human pregnancy. We recently proposed a role for maternal leukocytes in decidual spiral artery remodeling and suggested that matrix metalloprotease (MMP) activity contributed to the destruction of the arterial wall. In the current study we used our first trimester placental-decidual co-culture (PDC) model to define the temporal relationship and test the mechanistic aspects of this process. PDC experiments were assessed by image analysis over a six-day time-course for degree of vascular transformation and leukocyte distribution around progressively remodeled arterioles. We observed rapid transformation in PDCs associated with loss of vascular smooth muscle cells, widening of the vessel lumen, and significant accumulation of uterine Natural Killer cells and macrophages within the vascular wall (P < 0.001) before trophoblast presence in the vessel lumens. These events did not occur in decidua-only cultures. Active MMP-9 was detected in leukocytes and vascular cells of remodeling arterioles, and inhibition of MMP-2/9 activity in PDC resulted in failure of decidual vascular remodeling compared with vehicle-treated PDCs. Apoptosis of vascular cells, macrophage-mediated phagocytosis, and vascular smooth muscle cell dedifferentiation contributed to the remodeling observed. The PDC model indicates that placental presence is required to initiate decidual spiral artery remodeling but that uterine Natural Killer cells and macrophages mediate the early stages of this process at the cellular level.

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary

Amelioration of Penile Fibrosis: Myth or Reality

Several changes have been reported to occur in the cavernosal tissue and tunica albuginea with aging. The atherosclerosis of the penis that occurs with aging causes a decrease in penile oxygen tension. A reduction in the number of smooth muscle cells (SMCs) has been demonstrated in relation to this change in oxygen tension. Changes in the ratio of penile collagen have also been observed and could explain the decrease in penile elasticity and compliance with aging. Chronic ischemia is therefore associated with fibrosis but also with nitric oxide-cGMP reduction. The sensitivity of the α-adrenoceptors on the SMCs increases with aging. Furthermore, androgen deprivation produces penile tissue atrophy, alterations in dorsal nerve structure, alterations in endothelial morphology, reductions in trabecular SM content, increases in deposition of extracellular matrix, and increases in accumulation of adipocytes in the subtunical region of the corpus cavernosum. All of these modifications can explain the prevalence of erectile dysfunction with aging. The aim of this review is to address the underlying etiology of corporal fibrosis, especially aging, cavernosal nerve damage, androgen deprivation, and tunical fibrosis. Finally, we will address the proposed amelioration and reversal of fibrosis in terms of correcting, at least partially, the relative SMC loss that occurs with aging, diabetes, or cavernosal nerve damage and its impact on prevention of erectile dysfunction-associated cavernosal fibrosis.