Notch signaling is essential for vascular morphogenesis in mice

Krebs, Luke T.; Xue, Yun; Norton, Christine R.; Shutter, John R.; Maguire, Maureen; Sundberg, John P.; Gallahan, Daniel; Closson, Violaine; Kitajewski, Jan; Callahan, Robert; Smith, Gilbert H.; Stark, Kevin L.; Gridley, Thomas

doi:10.1101/gad.14.11.1343

Cited by 919 publications

(89 citation statements)

References 43 publications

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“…Once cleaved, this NICD translocates to the nucleus and activates target genes. Of interest, Notch function is linked to arterial differentiation [15,16]. More recently, Notch and its ligand Delta4 had emerged as the master regulator of tip cell selection and migration during endothelial sprouting [17].…”

Section: Angiogenic Factors: Vegf and Beyondmentioning

confidence: 99%

PAKing up to the endothelium

Moya

Guelte

Gavard

2009

Cellular Signalling

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Angiogenesis recapitulates the growth of blood vessels that progressively expand and remodel into a highly organized and stereotyped vascular network. During adulthood, endothelial cells that formed the vascular wall retain their plasticity and can be engaged in neo-vascularization in response to physiological stimuli, such as hypoxia, wound healing and tissue repair, ovarian cycle and pregnancy. In addition, numerous human diseases and pathological conditions are characterized by an excessive, uncontrolled and aberrant angiogenesis. The signalling pathways involving the small Rho GTPase, Rac and its downstream effector the p21-activated serine/threonine kinase (PAK) had recently emerged as pleiotropic modulators in these processes. Indeed, Rac and PAK were found to modulate endothelial cell biology, such as sprouting, migration, polarity, proliferation, lumen formation, and maturation. Elucidating the Rac/PAK molecular circuitry will provide essential information for the development of new therapeutic agents designed to normalize the blood vasculature in human diseases.

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Section: Angiogenic Factors: Vegf and Beyondmentioning

confidence: 99%

PAKing up to the endothelium

Moya

Guelte

Gavard

2009

Cellular Signalling

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“…It is unclear how Notch4 may be involved either in neuronal development or in the mature functioning of neurons. The targeted deletion of Notch4 in mice does not produce a detectable phenotype (Krebs et al 2000). In addition, in the mature brain, Notch4 is expressed at high levels in endothelial cells, but it is not present at detectable levels in mature neurons.…”

Section: “Developmental” Signaling Continues In the Adult Cnsmentioning

confidence: 99%

Neural Development, Cell-Cell Signaling, and the "Two-Hit" Hypothesis of Schizophrenia

Maynard

Sikich

Lieberman

et al. 2001

Schizophrenia Bulletin

343

201

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To account for the complex genetics, the developmental biology, and the late adolescent/early adulthood onset of schizophrenia, the "two-hit" hypothesis has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These early disruptions produce long-term vulnerability to a "second hit" that then leads to the onset of schizophrenia symptoms. The cell-cell signaling pathways involved in nonaxial induction, morphogenesis, and differentiation in the brain, as well as in the limbs and face, could be targets for a "first hit" during early development. These same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be targets for a "second hit" in the adolescent or adult brain. Furthermore, dysregulation of cell-cell signaling by a "first hit" may prime the CNS for a pathologic response to a "second hit" via the same signaling pathway. Thus, parallel disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

“…Notch3 is predominantly expressed in vascular SMC in humans [ 25 , 53 – 55 ]. It is a key regulator of vascular SMC phenotypes and is required for arterial identity and vascular SMC maturation [ 25 , 53 , 56 ]. Expression of the constitutively active Notch3 resulted in cell shape changes and an increase in α -actin [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome

Jespersen

Batra

et al. 2022

Journal of Immunology Research

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Background. The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiation in Marfan syndrome (MFS) is not completely understood. Methods. RNA-sequencing on ascending aortic tissue from a mouse model of MFS, Fbn1mgR/mgR, and wild-type controls was performed. Notch 3 expression and activation in aortic tissue were confirmed with real-time RT-PCR, immunohistochemistry, and Western blot. Fbn1mgR/mgR and wild-type mice were treated with a γ-secretase inhibitor, DAPT, to block Notch activation. Aortic aneurysms and rupture were evaluated with connective tissue staining, ultrasound, and life table analysis. Results. The murine RNA-sequencing data were validated with mouse and human MFS aortic tissue, demonstrating elevated Notch3 activation in MFS. Data further revealed that upregulation and activation of Notch3 were concomitant with increased expression of SMC contractile markers. Inhibiting Notch3 activation with DAPT attenuated aortic enlargement and improved survival of Fbn1mgR/mgR mice. DAPT treatment reduced elastin fiber fragmentation in the aorta and reversed the differentiation of SMCs. Conclusions. Our data demonstrated that matrix abnormalities in the aorta of MFS are associated with increased Notch3 activation. Enhanced Notch3 activation in MFS contributed to aortic aneurysm formation in MFS. This might be mediated by inducing a contractile phenotypic change of SMC. Our results suggest that inhibiting Notch3 activation may provide a strategy to prevent and treat aortic aneurysms in MFS.

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Notch signaling is essential for vascular morphogenesis in mice

Cited by 919 publications

References 43 publications

PAKing up to the endothelium

PAKing up to the endothelium

Neural Development, Cell-Cell Signaling, and the "Two-Hit" Hypothesis of Schizophrenia

Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome

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