Notch Signaling in Blood Vessels

Hofmann, Jennifer; Iruela‐Arispe, M. Luisa

doi:10.1161/01.res.0000266408.42939.e4

Cited by 197 publications

(72 citation statements)

References 147 publications

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“…Of particular interest is NOTCH3, a gene encoding one of the notch family members and known to be underlying cause of CADASIL [37,38]. NOTCH signaling is critical for maintenance of normal vascular structure, angiogenesis and vascular remodeling in both physiological and pathological conditions [39,40]. In our study we detected significant upregulation of NOTCH3 expression after eribulin treatment in HBVPs.…”

Section: Discussionsupporting

confidence: 54%

Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro

et al. 2014

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BackgroundEribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a tubulin-binding drug and approved in many countries worldwide for treatment of certain patients with advanced breast cancer. Here we investigated antiproliferative and antiangiogenic effects of eribulin on vascular cells, human umbilical vein endothelial cells (HUVECs) and human brain vascular pericytes (HBVPs), in vitro in comparison with another tubulin-binding drug, paclitaxel.MethodsHUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated. Global gene expression profiling changes caused by drug treatments were studied using Affymetrix microarray platform and custom TaqMan Low Density Cards. To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.ResultsBoth eribulin and paclitaxel showed potent activities in in vitro proliferation of HUVECs and HBVPs, with the half-maximal inhibitory concentrations (IC50) in low- to sub-nmol/L concentrations. When gene expression changes were assessed in HUVECs, the majority of affected genes overlapped for both treatments (59%), while in HBVPs, altered gene signatures were drug-dependent and the overlap was limited to just 12%. In HBVPs, eribulin selectively affected 11 pathways (p < 0.01) such as Cell Cycle Control of Chromosomal Replication. In contrast, paclitaxel was tended to regulate 27 pathways such as PI3K/AKT. Only 5 pathways were commonly affected by both treatments. In in vitro pericyte-driven angiogenesis model, paclitaxel showed limited activity while eribulin shortened the formed capillary networks of HUVECs driven by HBVPs at low nmol/L concentrations starting at day 3 after treatments.ConclusionsOur findings suggest that pericytes, but not endothelial cells, responded differently, to two mechanistically-distinct tubulin-binding drugs, eribulin and paclitaxel. While eribulin and paclitaxel induced similar changes in gene expression in endothelial cells, in pericytes their altered gene expression was unique and drug-specific. In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

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Section: Discussionsupporting

confidence: 54%

Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro

et al. 2014

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“…Notch signaling has well defined roles in embryonic vascular development, angiogenesis and arterial-venous specification 58 . In mammals, there are four distinct heterodimeric receptors, Notch1–Notch4, and five ligands, delta-like (DLL) 1, 3 and 4 and jagged (JAG) 1 and 2, all of which are transmembrane proteins.…”

Section: Signaling: Notchmentioning

confidence: 99%

Central nervous system pericytes in health and disease

2011

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Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.

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“…Establishing a cell-to-cell contact is a prerequisite for an efficient Notch signal transduction, as Notch forms heterodimeric transmembrane receptors with the transmembrane ligands delta-like (DLL) and jagged (JAG) on neighboring cells. Signal transduction is induced when the receptors and ligands bind, thus triggering the sequential proteolytic cleavage and release in the intracellular space the Notch intracellular domain (NICD), which translocates to the nucleus and binds the transcription factor recombination signal binding protein Jκ (RBPJκ), leading to downstream transcriptional changes [59]. More recently, it has been suggested that Notch signaling contribute to pericyte attachment and alignment at the abluminal side of brain endothelial cells, thus enhancing endothelial cell survival [60].…”

Section: Pericyte Interactions At the Neurovascular Unitmentioning

confidence: 99%

The Role of Pericytes in Neurovascular Unit Remodeling in Brain Disorders

ElAli

Thériault

Rivest

2014

IJMS

113

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Neurons are extremely vulnerable cells that tightly rely on the brain’s highly dynamic and complex vascular network that assures an accurate and adequate distribution of nutrients and oxygen. The neurovascular unit (NVU) couples neuronal activity to vascular function, controls brain homeostasis, and maintains an optimal brain microenvironment adequate for neuronal survival by adjusting blood-brain barrier (BBB) parameters based on brain needs. The NVU is a heterogeneous structure constituted by different cell types that includes pericytes. Pericytes are localized at the abluminal side of brain microvessels and contribute to NVU function. Pericytes play essential roles in the development and maturation of the neurovascular system during embryogenesis and stability during adulthood. Initially, pericytes were described as contractile cells involved in controlling neurovascular tone. However, recent reports have shown that pericytes dynamically respond to stress induced by injury upon brain diseases, by chemically and physically communicating with neighboring cells, by their immune properties and by their potential pluripotent nature within the neurovascular niche. As such, in this paper, we would like to review the role of pericytes in NVU remodeling, and their potential as targets for NVU repair strategies and consequently neuroprotection in two pathophysiologically distinct brain disorders: ischemic stroke and Alzheimer’s disease (AD).

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Notch Signaling in Blood Vessels

Cited by 197 publications

References 147 publications

Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro

Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro

Central nervous system pericytes in health and disease

The Role of Pericytes in Neurovascular Unit Remodeling in Brain Disorders

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