The Experts below are selected from a list of 156 Experts worldwide ranked by ideXlab platform
Matthew J. Pollman - One of the best experts on this subject based on the ideXlab platform.
-
Coordinate Notch3-Hairy-related Transcription Factor Pathway Regulation in Response to Arterial Injury MEDIATOR ROLE OF PLATELET-DERIVED GROWTH FACTOR AND ERK
The Journal of biological chemistry, 2002Co-Authors: Wenli Wang, Chengyu Z. Prince, Yongshan Mou, Alexandre H. Campos, Matthew J. PollmanAbstract:The Notch family of receptors and downstream effectors plays a critical role in cell fate determination during vascular ontogeny. Moreover, the human cerebral autosomal dominant artriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Syndrome of premature stroke and dementia is a heritable arteriopathy with alterations in vascular smooth muscle cells (VSMCs) resulting from mutations within Notch3. However, the expression and regulation of the Notch and hairy-related transcription factor (HRT) pathway in adult VSMCs in vitro and in vivo remain poorly characterized. The present study documents that the well-described modulation of VSMC fate in response to vascular injury and growth factor activation involves a coordinate regulation of the Notch and HRT pathways. Furthermore, platelet-derived growth factor promotes a similar coordinate down-regulation of the Notch receptors and HRT genes in cultured VSMCs via an ERK-dependent signaling pathway. Moreover, we established that HRT1 and HRT2 are direct downstream target genes of Notch3 signaling in VSMCs and determined that the activity of the nuclear protein RBP-Jk is essential for their regulation. These findings provide initial insight into the context- and cell type-dependent coordinate regulation of Notch3 and downstream HRT transcriptional pathway effector genes in VSMCs in vitro and in vivo that may have important implications for understanding the role of Notch signaling in human health and vascular disease.
-
Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.
The Journal of biological chemistry, 2002Co-Authors: Wenli Wang, Chengyu Z. Prince, Yongshan Mou, Matthew J. PollmanAbstract:Mutations in the Notch3 receptor result in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) Syndrome, a heritable arteriopathy predisposing to early onset stroke. Based upon clinical evidence that CADASIL arteriopathy results in degeneration and loss of vascular smooth muscle cells (VSMC) from the arterial wall, we postulated that Notch3 signaling is a critical determinant of VSMC survival. We initially established that both transient and constitutive Notch3 signaling promoted VSMC survival in response to the proapoptotic Fas ligand (FasL). Resistance to FasL-induced apoptosis was associated with the induction of c-FLIP, a primary inhibitor of the FasL signaling pathway. We determined that Notch3's regulation of c-FLIP was independent of the activity of the classical DNA-binding protein, RBP-Jk, but dependent upon cross-talk activation of the ERK/MAPK pathway. We extended our observations to the in vivo context by determining a coordinate regulation of Notch3 and c-FLIP within the arterial wall in response to injury. Furthermore, we defined that expression levels of Notch3 and c-FLIP are coordinately up-regulated within the neointima of remodeled arteries. Taken together, these findings provide initial evidence that Notch3 signaling may be a critical determinant of VSMC survival and vascular structure by modulating the expression of downstream mediators of apoptosis via signaling cross-talk with the ERK/MAPK pathway.
Cenk Ayata - One of the best experts on this subject based on the ideXlab platform.
-
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Syndrome Mutations Increase Susceptibility to Spreading Depression
Annals of neurology, 2011Co-Authors: Katharina Eikermann-haerter, Izumi Yuzawa, Ergin Dilekoz, Michael A. Moskowitz, Anne Joutel, Cenk AyataAbstract:Migraine with aura is often the first manifestation of CADASIL Syndrome, a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression, the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.
-
CADASIL experimental insights from animal models
Stroke, 2010Co-Authors: Cenk AyataAbstract:: 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.
Marina Scarpelli - One of the best experts on this subject based on the ideXlab platform.
-
Granular osmiophilic material-containing pseudoinclusions in CADASIL.
Journal of neuropathology and experimental neurology, 2014Co-Authors: Manrico Morroni, Teresa Lorenzi, Mario Castellucci, Michele Ragno, Marina ScarpelliAbstract:We recently described the role of electron microscopy examination in the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Syndrome in a retrospective study of 13 cases (1). In 1 patient who was homozygous for the G528C mutation (2), vascular smooth muscle cells (VSMCs) showed several cytoplasmic inclusions that were found to be granular osmiophilic material (GOM)–containing pseudoinclusions; the other 12 heterozygous patients did not seem to be affected. To determine whether GOM-containing pseudoinclusions are a pathognomonic sign of CADASIL Syndrome, particularly of the homozygous condition, we retrieved from our archives biopsy samples from all 13 patients (8 men and 5 women; age range, 45–64 years; mean, 53 years) with a diagnosis of CADASIL disease and re-examined them by electron microscopy to assess GOM-containing pseudoinclusions both qualitatively and quantitatively. Patients are listed in the Table; age, sex, sample type, molecular findings, and genotype are presented by Morroni et al (1). Patient 12 was homozygous for the G528C mutation (2). View this table: TABLE Extent of VSMC Branching and Proportion of Cells Showing GOM-Containing Pseudoinclusions in 13 CADASIL Patients Granular osmiophilic material–containing pseudoinclusions were quantified by examining 50 nucleated VSMCs or VSMCs devoid of the nucleus but containing abundant cytoplasm in small and medium arteries of each patient sample and by calculating the proportion of those bearing GOM-containing pseudoinclusions. Vascular smooth muscle cell cytoplasmic processes were not included in the calculation. Each pseudoinclusion was surrounded by a cell membrane and separated from it by an electron-lucent halo (Fig. A). The cytoplasmic membrane showed numerous pinocytotic vesicles (Fig. A) that …
-
Role of electron microscopy in the diagnosis of CADASIL Syndrome: a study of 32 patients.
PloS one, 2013Co-Authors: Manrico Morroni, Teresa Lorenzi, Mario Castellucci, Michele Ragno, Daniela Marzioni, Paolo Di Bella, Elisabetta Cartechini, Luigi Pianese, Marina ScarpelliAbstract:Background and Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations that result in vascular smooth muscle cell (VSMC) degeneration. Its distinctive feature by electron microscopy (EM) is granular osmiophilic material (GOM) detected in VSMC indentations and/or the extracellular space close to VSMCs. Reports of the sensitivity of EM in detecting GOM in biopsies from CADASIL patients are contradictory. We present data from 32 patients clinically suspected to have CADASIL and discuss the role of EM in its diagnosis in this retrospective study. Methods Skin, skeletal muscle, kidney and pericardial biopsies were examined by EM; the NOTCH3 gene was screened for mutations. Skin and muscle biopsies from 12 patients without neurological symptoms served as controls. Results and Discussion All GOM-positive patients exhibited NOTCH3 mutations and vice versa. This study i) confirms that EM is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of GOM distribution in tissues where it has never been described, e.g. pericardium; iii) documents a novel NOTCH3 mutation in exon 3; and iv) shows that EM analysis is critical to highlight the need for comprehensive NOTCH3 analysis. Our findings also confirm the genetic heterogeneity of CADASIL in a small Italian subpopulation and emphasize the difficulties in designing algorithms for molecular diagnosis.
Wenli Wang - One of the best experts on this subject based on the ideXlab platform.
-
Coordinate Notch3-Hairy-related Transcription Factor Pathway Regulation in Response to Arterial Injury MEDIATOR ROLE OF PLATELET-DERIVED GROWTH FACTOR AND ERK
The Journal of biological chemistry, 2002Co-Authors: Wenli Wang, Chengyu Z. Prince, Yongshan Mou, Alexandre H. Campos, Matthew J. PollmanAbstract:The Notch family of receptors and downstream effectors plays a critical role in cell fate determination during vascular ontogeny. Moreover, the human cerebral autosomal dominant artriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Syndrome of premature stroke and dementia is a heritable arteriopathy with alterations in vascular smooth muscle cells (VSMCs) resulting from mutations within Notch3. However, the expression and regulation of the Notch and hairy-related transcription factor (HRT) pathway in adult VSMCs in vitro and in vivo remain poorly characterized. The present study documents that the well-described modulation of VSMC fate in response to vascular injury and growth factor activation involves a coordinate regulation of the Notch and HRT pathways. Furthermore, platelet-derived growth factor promotes a similar coordinate down-regulation of the Notch receptors and HRT genes in cultured VSMCs via an ERK-dependent signaling pathway. Moreover, we established that HRT1 and HRT2 are direct downstream target genes of Notch3 signaling in VSMCs and determined that the activity of the nuclear protein RBP-Jk is essential for their regulation. These findings provide initial insight into the context- and cell type-dependent coordinate regulation of Notch3 and downstream HRT transcriptional pathway effector genes in VSMCs in vitro and in vivo that may have important implications for understanding the role of Notch signaling in human health and vascular disease.
-
Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.
The Journal of biological chemistry, 2002Co-Authors: Wenli Wang, Chengyu Z. Prince, Yongshan Mou, Matthew J. PollmanAbstract:Mutations in the Notch3 receptor result in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) Syndrome, a heritable arteriopathy predisposing to early onset stroke. Based upon clinical evidence that CADASIL arteriopathy results in degeneration and loss of vascular smooth muscle cells (VSMC) from the arterial wall, we postulated that Notch3 signaling is a critical determinant of VSMC survival. We initially established that both transient and constitutive Notch3 signaling promoted VSMC survival in response to the proapoptotic Fas ligand (FasL). Resistance to FasL-induced apoptosis was associated with the induction of c-FLIP, a primary inhibitor of the FasL signaling pathway. We determined that Notch3's regulation of c-FLIP was independent of the activity of the classical DNA-binding protein, RBP-Jk, but dependent upon cross-talk activation of the ERK/MAPK pathway. We extended our observations to the in vivo context by determining a coordinate regulation of Notch3 and c-FLIP within the arterial wall in response to injury. Furthermore, we defined that expression levels of Notch3 and c-FLIP are coordinately up-regulated within the neointima of remodeled arteries. Taken together, these findings provide initial evidence that Notch3 signaling may be a critical determinant of VSMC survival and vascular structure by modulating the expression of downstream mediators of apoptosis via signaling cross-talk with the ERK/MAPK pathway.
Deniz Selcuki - One of the best experts on this subject based on the ideXlab platform.
-
CADASIL with Atypical Clinical Symptoms, Magnetic Resonance Imaging, and Novel Mutations: Two Case Reports and a Review of the Literature
Journal of Molecular Neuroscience, 2019Co-Authors: U. Serpil Sari, And N. Coskunoglu, Aysin Kisabay, Melike Batum, Serdar Tarhan, Nihal Dogan, Sirri Cam, Hikmet Yilmaz, Deniz SelcukiAbstract:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy with adult onset caused by a missense mutation in the NOTCH3 gene in chromosome 19p13. It presents with autosomal dominant arteriopathy, subcortical infarctions, and leukoencephalopathy. Its common clinical presentations are seen as recurrent strokes, migraine or migraine-like headaches, progressive dementia, pseudobulbar paralysis, and psychiatric conditions. Two patients with CADASIL Syndrome, whose diagnosis was made based on clinical course, age of onset, imaging findings, and genetic assays in the patients and family members, are presented here because of new familial polymorphisms. The first patient, with cerebellar and psychotic findings, had widespread non-confluent hyperintense lesions as well as moderate cerebellar atrophy in cranial magnetic resonance scanning. The other patient, with headache, dizziness, and forgetfulness, had gliotic lesions in both cerebral hemispheres. CADASIL gene studies revealed a new polymorphism in exon 33 in the first patient. In the other patient, the NOTCH3 gene was identified as a new variant of p.H243P (c.728A > C heterozygous). By reporting a family presenting with various clinical symptoms in the presence of new polymorphisms, we emphasize that CADASIL Syndrome may present with various clinical courses and should be considered in differential diagnoses.
