transforming-growth-factor-beta and Intracranial-Aneurysm

Patients with connective tissue diseases (CTDs) are suspected to be at higher risk for cerebrovascular involvement, such as intracranial aneurysms, dissections and strokes, than the general population. Particularly, Marfan Syndrome (MFS) has been reported as associated with an increased risk of cerebrovascular alterations. Literature data report different prevalence of intracranial aneurysms in MFS, ranging from 4 % to 29 %, suggesting a role of genetic cause that involves the regulation of the TGF-β signaling. Ischemic and hemorrhagic strokes have been also reported in MFS, but with an estimated prevalence from 3 % to 4 %. However, the aetiology of both events appears to be reliable more to a cardiac source than to the primary connective tissue defect. Finally, the available literature suggests that MFS patients have a higher prevalence of arterial tortuosity of neck and head vessels and these findings may be related to an enhanced chance of dissection. Overall, despite of the lack of studies, we could affirm that it may exists an increased prevalence of some neurovascular findings in MFS patients. Nevertheless, further studies are required to determine the true prevalence of these features and investigate specific gene mutations involved in MFS.

Topics: Arteries; Hemorrhagic Stroke; Humans; Intracranial Aneurysm; Ischemic Stroke; Joint Instability; Marfan Syndrome; Prevalence; Signal Transduction; Skin Diseases, Genetic; Transforming Growth Factor beta; Vascular Malformations

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2-5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

Topics: Aneurysm, Ruptured; Animals; Arteritis; Case-Control Studies; Cerebral Arteries; Disease Models, Animal; Endothelial Cells; Exome Sequencing; Focal Adhesions; Genetic Predisposition to Disease; Genome-Wide Association Study; Hemorheology; Humans; Incidence; Intracranial Aneurysm; Mammals; Mechanotransduction, Cellular; Mice; Myocytes, Smooth Muscle; SOXF Transcription Factors; Subarachnoid Hemorrhage; Syndrome; Thrombospondins; Transforming Growth Factor beta; Zebrafish

Topics: Aortic Aneurysm; Elasticity; Hemodynamics; Humans; Intracranial Aneurysm; Organ Specificity; Risk Factors; Transforming Growth Factor beta

The molecular mechanisms behind the rupture of intracranial aneurysms remain obscure. MiRNAs are key regulators of a wide array of biological processes altering protein synthesis by binding to target mRNAs. However, variations in miRNA levels in ruptured aneurysmal wall have not been completely examined. We hypothesized that altered miRNA signature in aneurysmal tissues could potentially provide insight into aneurysm pathophysiology. Using a high-throughput miRNA microarray screening approach, we compared the miRNA expression pattern in aneurysm tissues obtained during surgery from patients with aneurysmal subarachnoid hemorrhage (aSAH) with control tissues (GEO accession number GSE161870). We found that the expression of 70 miRNAs was altered. Expressions of the top 10 miRNA were validated, by qRT-PCR and results were correlated with clinical characteristics of aSAH patients. The level of 10 miRNAs (miR-24-3p, miR-26b-5p, miR-27b-3p, miR-125b-5p, miR-143-3p, miR-145-5p, miR-193a-3p, miR-199a-5p, miR-365a-3p/365b-3p, and miR-497-5p) was significantly decreased in patients compared to controls. Expression of miR-125b-5p, miR-143-3p and miR-199a-5p was significantly decreased in patients with poor prognosis and vasospasm. The target genes of few miRNAs were enriched in Transforming growth factor-beta (TGF-β) and Mitogen-activated protein kinases (MAPK) pathways. We found significant negative correlation between the miRNA and mRNA expression (TGF-β1, TGF-β2, SMAD family member 2 (SMAD2), SMAD family member 4 (SMAD4), MAPK1 and MAPK3) in aneurysm tissues. We suggest that miR-26b, miR-199a, miR-497and miR-365, could target multiple genes in TGF-β and MAPK signaling cascades to influence inflammatory processes, extracellular matrix and vascular smooth muscle cell degradation and apoptosis, and ultimately cause vessel wall degradation and rupture.

Topics: Gene Expression Profiling; Humans; Intracranial Aneurysm; MicroRNAs; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Patients with intracranial aneurysm (IA) present a dysregulated immune system with lower frequency of regulatory T (Treg) cells. Here, we examined whether galectin 9 (Gal-9), the natural ligand of Tim-3, could promote Treg cells in IA patients. We first discovered that the intracellular and extracellular Gal-9 was primarily expressed by CD4

Topics: Adult; Case-Control Studies; Down-Regulation; Female; Galectins; Hepatitis A Virus Cellular Receptor 2; Humans; Interleukin-10; Intracellular Space; Intracranial Aneurysm; Macrophages; Male; Middle Aged; Monocytes; Solubility; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

This study aimed to deliver gellan sulfate core platinum coil with tenascin-C (GSCC-TNC) into rabbit side-wall aneurysms endovascularly and to evaluate the organization effects in a simulated clinical setting.. Elastase-induced rabbit side-wall aneurysms were randomly coiled via a transfemoral route like clinical settings with platinum coils (PCs), gellan sulfate core platinum coils (GSCCs), or GSCC-TNCs (n = 5, respectively). Aneurysm-occlusion status was evaluated angiographically and histologically at 2 weeks post coiling. As each rabbit coiled aneurysm provided only 2-3 tissue slices due to technical limitations and prevented immunohistochemical evaluations, a PC, GSCC, or GSCC-TNC was randomly implanted in a rat blind-ended model (n = 3, respectively) and the organization effects were immunohistochemically evaluated for expressions of tenascin-C (TNC), transforming growth factor-beta (TGF-β), and matrix metalloproteinase-9 (MMP-9) 2 weeks later.. Coil handling was similar among the 3 kinds of coils. GSCCs showed a significantly higher ratio of organized area to the aneurysmal cavity than PCs, but GSCC-TNCs had the greatest organization-promoting effects on aneurysms (the ratio of organized area/aneurysmal luminal area: PC, 17.9 ± 7.1%; GSCC, 54.2 ± 18.3%; GSCC-TNC, 82.5 ± 5.8%). GSCC-TNCs had intense immunoreactivities for TNC, TGF-β, and MMP-9 in the organized thrombosis and tunica media. GSCCs also showed intense immunoreactivities for TNC, TGF-β, and MMP-9, although the extent was less than GSCC-TNCs. The immunoreactivities were hardly found in unorganized thrombus and the tunica media of aneurysm wall in the PC group.. This study first showed that GSCC-TNCs promote intra-aneurysmal clot organization in simulated clinical settings using rabbits possibly through the TGF-β and MMP-9 upregulation.

Topics: Angiography; Animals; Cell Line, Tumor; Disease Models, Animal; Embolization, Therapeutic; Female; Glioma; Intracranial Aneurysm; Male; Matrix Metalloproteinase 9; Platinum; Polysaccharides; Rabbits; Rats; Rats, Sprague-Dawley; Sulfuric Acid Esters; Tenascin; Transforming Growth Factor beta

The identification of significant individual factors causing complex diseases is challenging in genome-wide association studies (GWAS) since each factor has only a modest effect on the disease development mechanism. In this study, we hypothesize that the biological pathways that are targeted by these individual factors show higher conservation within and across populations. To test this hypothesis, we searched for the disease related pathways on two intracranial aneurysm GWAS in European and Japanese case-control cohorts. Even though there were a few significantly conserved SNPs within and between populations, seven of the top ten affected pathways were found significant in both populations. The probability of random occurrence of such an event is 2.44E-36. We therefore claim that even though each individual has a unique combination of factors involved in the mechanism of disease development, most targeted pathways that need to be altered by these factors are, for the most part, the same. These pathways can serve as disease markers. Individuals, for example, can be scanned for factors affecting the genes in marker pathways. Hence, individual factors of disease development can be determined; and this knowledge can be exploited for drug development and personalized therapeutic applications. Here, we discuss the potential avenues of pathway markers in medicine and their translation to preventive and individualized health care.

Topics: Asian People; Biomarkers; Calcium Signaling; Genetic Predisposition to Disease; Genetics, Population; Genome-Wide Association Study; Humans; Intracranial Aneurysm; MAP Kinase Signaling System; Polymorphism, Single Nucleotide; Signal Transduction; Transforming Growth Factor beta; White People

Cellular adhesion on the surface of Guglielmi detachable coils (GDC) promotes accelerated occlusion of aneurysms. We hypothesized that coils coated with transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF) will promote clot organization and endothelial or cellular proliferation to facilitate closure of large experimental aneurysms relative to uncoated GDC coils.. GDC were inserted either uncoated, coated with albumin, coated with TGF-beta (500 μg/ml) or with VEGF (500 μg/ml) into the ligated common carotid artery of adult male wistar rats for 14 days. Twenty-four adult male Wistar rats (280-300 g) were divided into four groups (n = 6 per group). Subjects were killed 2 weeks after implantation and common carotid artery (CCA) segments were harvested and coils were removed. Arterial tissue was evaluated histopathologically.. Significant differences in the proportion of aneurysm luminal area (mm(2)) was shown among Group i (0·22±0·14 SD) and Group ii (0·16±0·8 SD) compared to Group iii (0·04±0·03 SD; P<0·05), and Group iv (0·02±0·02 SD; P<0·05) analyzed 2 weeks postoperatively. Light microscopy showed well organized fibrous tissue formation of epithelial cells and intimal hyperplasia around the coils when using the coated GDC's (Group iii and Group iv).. The result of this study suggests that the coated GDC with TGF-beta or VEGF appears beneficial in promoting endothelization, clot organization, and cellular tissue integration of the coils.

Topics: Analysis of Variance; Animals; Carotid Artery, Common; Coated Materials, Biocompatible; Disease Models, Animal; Embolization, Therapeutic; Endothelium, Vascular; Intracranial Aneurysm; Male; Microscopy, Atomic Force; Prostheses and Implants; Rats; Rats, Wistar; Transforming Growth Factor beta; Treatment Outcome; Vascular Endothelial Growth Factor A

Familial aggregation of intracranial aneurysms (IA) strongly suggests a genetic contribution to pathogenesis. However, genetic risk factors have yet to be defined. For families affected by aortic aneurysms, specific gene variants have been identified, many affecting the receptors to transforming growth factor-beta (TGF-beta). In recent work, we found that aortic and intracranial aneurysms may share a common genetic basis in some families. We hypothesized, therefore, that mutations in TGF-beta receptors might also play a role in IA pathogenesis.. To identify genetic variants in TGF-beta and its receptors, TGFB1, TGFBR1, TGFBR2, ACVR1, TGFBR3, and ENG were directly sequenced in 44 unrelated patients with familial IA. Novel variants were confirmed by restriction digestion analyses, and allele frequencies were analyzed in cases versus individuals without known intracranial disease. Similarly, allele frequencies of a subset of known SNPs in each gene were also analyzed for association with IA.. No mutations were found in TGFB1, TGFBR1, TGFBR2, or ACVR1. Novel variants identified in ENG (p.A60E) and TGFBR3 (p.W112R) were not detected in at least 892 reference chromosomes. ENG p.A60E showed significant association with familial IA in case-control studies (P=0.0080). No association with IA could be found for any of the known polymorphisms tested.. Mutations in TGF-beta receptor genes are not a major cause of IA. However, we identified rare variants in ENG and TGFBR3 that may be important for IA pathogenesis in a subset of families.

Topics: Activin Receptors, Type I; Aged; Alleles; Antigens, CD; DNA; DNA Primers; Endoglin; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Proteoglycans; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Signal Transduction; Stroke; Transforming Growth Factor beta

The 19q13.3 locus for intracranial aneurysms (IA) partly overlaps with the 19q13 locus for abdominal aortic aneurysms (AAA). A common genetic risk factor located in this locus for the two aneurysm types seems plausible. The transforming growth factor beta (TGF-beta) signalling pathway plays a role in aortic aneurysms but may also play a role in aneurysms in general. In the combined region of the 19q13 loci for IA and AAA we identified two candidate genes that are both involved in the TGF-beta signalling pathway: hepsin (HPN) and the latent transforming growth factor beta-binding protein 4 (LTBP4). We hypothesised that single nucleotide polymorphisms (SNP) in the HPN and LTBP4 genes are associated with IA.. We analyzed all the common variations using tag SNP in the HPN and LTBP4 genes for association with IA in 390 patients and 642 controls in the Dutch population. Six tag SNP in the HPN gene and five tag SNP in the LTBP4 gene were genotyped.. No differences in SNP frequency were observed for both the HPN and LTBP4 gene between patients and controls.. Our findings suggest that variations in or near the HPN and LTBP4 genes do not play a role in the susceptibility to IA in the Dutch population.

Topics: Adult; Aged; Aged, 80 and over; Aneurysm, Ruptured; Aortic Aneurysm, Abdominal; Chromosome Mapping; Chromosomes, Human, Pair 19; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Humans; Intracranial Aneurysm; Latent TGF-beta Binding Proteins; Male; Middle Aged; Netherlands; Polymorphism, Single Nucleotide; Serine Endopeptidases; Signal Transduction; Subarachnoid Hemorrhage; Transforming Growth Factor beta

The authors attempted to identify genes associated with healing or recurrence after embolization in an aneurysm model in which neointima formation at the neck varies according to flow zones. A better understanding of the relationship between blood flow, molecular events, and healing or recurrence may provide future avenues to improve results of endovascular treatment of aneurysms.. Bilateral carotid venous pouch aneurysms were constructed in 36 dogs and embolized with gelatin sponges. Angiography and pathological studies were performed at T0 and/or 3 weeks (n=22). Angiographic results and neointima formation were scored using a qualitative index applied to the distal (inflow) and proximal (outflow) zones of the neck. In 14 animals, mRNA expression 1 to 14 days after embolization at the proximal or distal segment of the sponge was analyzed by RT-PCR, attempting to correlate flow zones, gene expression, and neointima formation.. Aneurysms recurred at 3 weeks, as shown by significantly worse angiographic scores as compared to T0 (P<.01). Neointimal scores differed at pathology, with a more complete neointima at the proximal as compared to the distal aspect of the sponge at 3 weeks (P=.027). Embolization was followed by migration of CD31+, CD14+, smooth muscle alpha-actin+ (SMA+) cells that progressively expressed metalloproteinases (MMP-9,-12,-14), but stable or lesser, retarded expression of inhibitors (TIMP1-4). Growth factors (PDGF-BB, TGF-beta1, TNF-alpha, MCP-1 and Ang-1) were expressed at increasing levels, maximal at 7 to 14 days. Differences between distal and proximal zones were limited to increased expression of MMP-2 proximally (P<.035).. Gene expression after embolization is compatible with patterns associated with neointima formation. The authors have not identified key factors involved in recurrence.

Topics: Actins; Angiotensin I; Animals; Becaplermin; Cerebral Angiography; Chemokine CCL2; Disease Models, Animal; Dogs; Embolization, Therapeutic; Gelatin Sponge, Absorbable; Gene Expression; Hemostatics; Intracranial Aneurysm; Lipopolysaccharide Receptors; Matrix Metalloproteinases; Muscle, Smooth, Vascular; Neck; Platelet Endothelial Cell Adhesion Molecule-1; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Recurrence; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Tunica Intima; Vascular Surgical Procedures

To test the hypothesis that coating platinum coils with transforming growth factor beta (TGFbeta) would improve the cellular proliferation within experimental aneurysms relative to uncoated coils.. Elastase-induced saccular aneurysms were created in 12 New Zealand White rabbits. These aneurysms were embolized with platinum coils, either "control" (unmodified) coils or "test" (coated with TGFbeta) coils. Subjects were killed either 2 weeks (n = 3, control; n = 3, test) or 6 weeks (n = 3, control; n = 3, test) after embolization. Aneurysm tissue was embedded in plastic, sectioned, and stained with hematoxylin and eosin. The thickness of tissue covering the coils at the coil-lumen interface was measured by use of a digital microscope, and was compared between groups by use of the Student's t test (P < or = 0.05).. Two-week implantation samples demonstrated mean thickness of tissue overlying TGFbeta-coated coils of 36+/-15 microm and mean thickness of overlying control coils of 3+/-5 microm, indicating significantly thicker tissue growth covering test versus control coils (P = 0.02). Six-week implantation samples demonstrated mean thickness of tissue overlying TGFbeta-coated coils of 86+/-74 microm versus mean thickness overlying control coils of 37+/-6 mu; this difference did not reach statistical significance (P = 0.30). Thickness of tissue covering TGFbeta-coated coils did not change significantly from 2 to 6 weeks (P = 0.31). Tissue thickness over control coils increased significantly between 2 and 6 weeks (P = 0.002).. TGFbeta-coated platinum coils undergo earlier cellular coverage than standard platinum coils, but differences in coverage between coated and control coils are no longer present at later time points. These data suggest that improvements in intra-aneurysmal cellular proliferation resulting from coil modifications, although significant in the early postembolization phase, may dissipate over time.

Topics: Animals; Biotransformation; Blood Vessel Prosthesis; Cell Division; Disease Models, Animal; Embolization, Therapeutic; Equipment Design; Intracranial Aneurysm; Muscle, Smooth, Vascular; Platinum; Rabbits; Transforming Growth Factor beta

Postoperative infections are common and potentially fatal complications in neurosurgical intensive care medicine. An impairment of immune function has been described after central nervous system surgery and in patients harboring malignant brain tumors. The aim of our study was to investigate whether differences in cell-mediated immunity can be found in patients undergoing craniotomy for surgery of glioblastoma or clipping of an intracerebral aneurysm.. In order to determine the influence of the underlying disease on the immune system, we measured changes in cytokine concentrations (IL-6, IL-10, TGF-beta1) and lymphocyte-subsets (CD3+, CD3+HLA-DR+, CD4+, CD8+, CD19+, and CD16+56+) in 8 patients with glioblastoma and in 8 patients with an intracerebral aneurysm before, during and after the neurosurgical procedure.. In the comparison of glioblastoma and aneurysm patients, we could show that IL-6 plasma levels were pre- and intraoperatively higher in the aneurysm-group (P<0.05), and the plasma concentrations of IL-10 and TGF-beta were significantly elevated in the glioma-group. The lymphocyte-subsets showed a significantly lower percentage of NK-cells and activated T-cells in the glioma-group.. Our results document a significant dysregulation of immune response in glioma patients. This may be induced by elevated plasma concentrations of immunoinhibiting cytokines IL-10 and transforming growth factor-beta 1.

Topics: Brain Neoplasms; Craniotomy; Female; Glioblastoma; Humans; Immunity, Cellular; Interleukins; Intracranial Aneurysm; Lymphocyte Count; Lymphocyte Subsets; Male; Middle Aged; Postoperative Complications; Transforming Growth Factor beta