Von Willebrand Factor Inhibits Mature Smooth Muscle Gene Expression through Impairment of Notch Signaling

Meng, He; Zhang, Xiaojie; Lee, Soo Jung; Wang, Michael M.

doi:10.1371/journal.pone.0075808

Cited by 16 publications

(12 citation statements)

References 53 publications

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“…Notch activity has since been shown to directly promote the transcription of ACTA2 (Noseda et al, 2006), and Notch-induced transcription of ACTA2 was repressed by HRT transcription factors (Tang, Urs, & Liaw, 2008). Overall, the preponderance of data supports the hypothesis that Notch signaling in VSMCs promotes contractile differentiation (Baeten et al, 2015; Boscolo et al, 2011; Boucher, Gridley, & Liaw, 2012; Doi et al, 2006; Domenga et al, 2004; High et al, 2008, 2007; Lin & Lilly, 2014b; Liu et al, 2010; Meng, Zhang, Lee, & Wang, 2013; Noseda et al, 2006; Tang et al, 2010; Wang et al, 2012), which fits with our understanding of its role in development of the vessel wall and response to contact-induced signaling with endothelial cells (Baeten et al, 2015; Gaengel, Genove, Armulik, & Betsholtz, 2009; High et al, 2008; Hoglund & Majesky, 2012; Lilly & Kennard, 2009; Lin & Lilly, 2014a, 2014b; Liu et al, 2009; Manderfield et al, 2012; Regan & Majesky, 2009; Wang et al, 2012). …”

Section: Notch Signaling and Vsmc Phenotypesupporting

confidence: 58%

Notch Signaling in Vascular Smooth Muscle Cells

Baeten

Lilly

2017

Advances in Pharmacology

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The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

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Section: Notch Signaling and Vsmc Phenotypesupporting

confidence: 58%

Notch Signaling in Vascular Smooth Muscle Cells

Baeten

Lilly

2017

Advances in Pharmacology

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“…In adults, NOTCH3 expression is primarily within myocytes. Clinical studies of CADASIL support the notion of a relatively intact endothelium in the presence of SVD vasculopathy .…”

Section: What Is Small Vessel Disease (Svd)?mentioning

confidence: 79%

Endothelial Cells and Human Cerebral Small Vessel Disease

2014

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Brain endothelial cells have unique properties in terms of barrier function, local molecular signaling, regulation of local cerebral blood flow (CBF) and interactions with other members of the neurovascular unit. In cerebral small vessel disease (arteriolosclerosis; SVD), the endothelial cells in small arteries survive, even when mural pathology is advanced and myocytes are severely depleted. Here, we review aspects of altered endothelial functions that have been implicated in SVD: local CBF dysregulation, endothelial activation and blood-brain barrier (BBB) dysfunction. Reduced CBF is reported in the diffuse white matter lesions that are a neuroradiological signature of SVD. This may reflect an underlying deficit in local CBF regulation (possibly via the nitric oxide/cGMP signaling pathway). While many laboratories have observed an association of symptomatic SVD with serum markers of endothelial activation, it is apparent that the origin of these circulating markers need not be brain endothelium. Our own neuropathology studies did not confirm local endothelial activation in small vessels exhibiting SVD. Local BBB failure has been proposed as a cause of SVD and associated parenchymal lesions. Some groups find that computational analyses of magnetic resonance imaging (MRI) scans, following systemic injection of a gadolinium-based contrast agent, suggest that extravasation into brain parenchyma is heightened in people with SVD. Our recent histochemical studies of donated brain tissue, using immunolabeling for large plasma proteins [fibrinogen, immunoglobulin G (IgG)], do not support an association of SVD with recent plasma protein extravasation. It is possible that a trigger leakage episode, or a size-selective loosening of the BBB, participates in SVD pathology.

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“…Of note, several additional proteins that build up in CADASIL vessels have been shown to physically interact with NOTCH3 protein (eg. vWF [41], collagen [42], TIMP3 [35], and NOTCH3 itself [31]). The binding of BGN to both NOTCH3 and collagen suggests the possibility that complex multimolecular complexes may form in CADASIL.…”

Section: Discussionmentioning

confidence: 99%

The Small Leucine-Rich Proteoglycan BGN Accumulates in CADASIL and Binds to NOTCH3

Zhang

Lee

Young

et al. 2015

Transl. Stroke Res.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited form of cerebral small vessel disease caused by mutations in conserved residues of NOTCH3. Affected arteries of CADASIL feature fibrosis and accumulation of NOTCH3. A variety of collagen subtypes (types I, III, IV, and VI) have been identified in fibrotic CADASIL vessels. Biglycan (BGN) and decorin (DCN), are Class I members of the small leucine-rich proteoglycan (SLRP) family that regulate collagen fibril size. Because DCN has been shown to deposit in arteries in cerebral small vessel disease, we tested whether BGN accumulates in arteries of CADASIL brains. BGN was strongly expressed in both small penetrating and leptomeningeal arteries of CADASIL brain. BGN protein was localized to all three layers of arteries (intima, media, and adventitia). Substantially more immunoreactivity was observed in CADASIL brains compared to controls. Immunoblotting of brain lysates showed a 4-fold increase in CADASIL brains (compared to controls). Messenger RNA encoding BGN was also increased in CADASIL and was localized by in situ hybridization to all three vascular layers in CADASIL. Human cerebrovascular smooth muscle cells exposed to purified NOTCH3 ectodomain upregulated BGN, DCN, and COL4A1 through mechanisms that are sensitive to rapamycin, a potent mTOR inhibitor. In addition, BGN protein interacted directly with NOTCH3 protein in cell culture and in direct protein interaction assays. In conclusion, BGN is a CADASIL-enriched protein that potentially accumulates in vessels by mTOR-mediated transcriptional activation and/or post-translational accumulation via protein interactions with NOTCH3 and collagen.

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Von Willebrand Factor Inhibits Mature Smooth Muscle Gene Expression through Impairment of Notch Signaling

Cited by 16 publications

References 53 publications

Notch Signaling in Vascular Smooth Muscle Cells

Notch Signaling in Vascular Smooth Muscle Cells

Endothelial Cells and Human Cerebral Small Vessel Disease

The Small Leucine-Rich Proteoglycan BGN Accumulates in CADASIL and Binds to NOTCH3

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