Expression of platelet-derived growth factor ligand and receptor in cerebral arteriovenous and cavernous malformations

Yıldırım, Özlem; Biçer, Atilla; Ozkan, Abdulkadir; Kurtkaya, Özlem; Cirakoglu, Beyazid; Kılıç, Türker

doi:10.1016/j.jocn.2010.04.028

Cited by 22 publications

(17 citation statements)

References 32 publications

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“…8 On the other hand, only a few cases of de novo cerebral AVMs have been identified and published. 1,4,8,11,14,20,22 In an interesting article, Park et al 15 showed real-time images in the birth and growth of a de novo subdermal AVM in an adult mouse model of HHT with an ALK1 mutation and demonstrated that in addition to the genetic defect (first hit), a second hit (a vascular injury in Park and colleagues' article) is required to induce a morphologically visible AVM.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism for the second hit is also invoked for other cerebral vascular malformations such as CCM. 13,21,22 Some authors underline the likelihood of somatic epigenetic changes involved in sporadic lesions. 7 Cerebral cavernous malformations are venous malformations composed of sinusoidal vascular spaces lined by a single layer of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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De novo cerebral arteriovenous malformation in a child with previous cavernous malformation and developmental venous anomaly

Álvarez

Perry²,

Solle

et al. 2012

PED

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Although cerebral vascular malformations are traditionally considered to be congenital lesions, they often become clinically evident in the 3rd to 4th decades of life, leading to the assumption of a long silent clinical period. Unlike vein of Galen malformations, antenatal diagnosis of cerebral arteriovenous malformations (AVMs) is highly uncommon. Postnatal development of an AVM is an emergent concept supported by more clinical observations. Genetic and biological studies demonstrate that an environmental trigger (“second hit”) in addition to genetic predisposition may be a key in understanding the pathophysiology of AVMs and other cerebral vascular lesions such as cavernous malformations (CMs). The authors describe a 6-year-old boy in whom a giant CM was diagnosed and a de novo AVM was detected 25 months after initial resection of the CM. This case seems to support the second-hit hypothesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

De novo cerebral arteriovenous malformation in a child with previous cavernous malformation and developmental venous anomaly

Álvarez

Perry²,

Solle

et al. 2012

PED

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“…Nonetheless, increased expression of several pro-angiogenic growth factors have been found in human CCM lesions, including VEGF, PDGF, and TGF-β (Abe et al, 2009, Jung et al, 2003, Maiuri et al, 2006, Yildirim et al, 2010), and increased VEGF expression has also been measured in KRIT1 deficient animals (Corr et al, 2012). DiStefano et al showed that loss of KRIT1 increases VEGF expression by increasing nuclear β-catenin (DiStefano et al, 2014), where β-catenin stimulates transcription of VEGF (Glading and Ginsberg, 2010).…”

Section: Role Of Angiogenesis In Ccm Pathogenesismentioning

confidence: 99%

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

110

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Graphical abstractTowards a unifying mechanism for CCM disease pathogenesis and treatment.CCM proteins play pleiotropic roles in distinct redox-sensitive pathways by modulating the fine-tuned crosstalk between redox signaling and autophagy. Effective autophagy removes ROS-generating cellular trash, including damaged mitochondria, to rejuvenate cell environment, thus serving a cytoprotective function for the maintenance of endothelial cell monolayer integrity and functionality and blood–brain barrier (BBB) stability even under adverse stress conditions. Loss-of-function of a CCM protein (e.g., KRIT1) causes defective autophagy and altered redox signaling, affecting BBB stability and sensitizing endothelial cells to local oxidative stress and inflammatory events, which may act as key pathogenic determinants of focal formation and progression of CCM lesions. The common capacity to modulate the interplay between autophagy and redox signaling reconciles the distinct pharmacological approaches proposed so far for CCM disease prevention and treatment.

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“…17,34 Histopathologic findings provided evidence of elevated levels of PDGF in CCM lesions. 35,36 Considering that the PDGFβ receptor is downregulated on decreased Notch3 activity in pericytes, this can be seen as a compensatory mechanism.…”

Section: May 2015mentioning

confidence: 99%

Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes

Schulz

Wieland

Wüstehube-Lausch

et al. 2015

Stroke

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Background and Purpose— Cerebral cavernous malformation (CCM) is a neurovascular dysplasia characterized by conglomerates of enlarged endothelial channels in the central nervous system, which are almost devoid of pericytes or smooth muscle cells. This disease is caused by loss-of-function mutations in CCM1 , CCM2 , or CCM3 genes in endothelial cells, making blood vessels highly susceptible to angiogenic stimuli. CCM1 - and CCM3 -silenced endothelial cells have a reduced expression of the Notch ligand Delta-like 4 (DLL4) resulting in impaired Notch signaling and irregular sprouting angiogenesis. This study aimed to address if DLL4, which is exclusively expressed on endothelial cells, may influence interactions of endothelial cells with pericytes, which express Notch3 as the predominant Notch receptor. Methods— Genetic manipulation of primary human endothelial cells and brain pericytes. Transgenic mouse models were also used. Results— Endothelial cell–specific ablation of Ccm1 and Ccm2 in different mouse models led to the formation of CCM-like lesions, which were poorly covered by periendothelial cells. CCM1 silencing in endothelial cells caused decreased Notch3 activity in cocultured pericytes. DLL4 proteins stimulated Notch3 receptors on human brain pericytes. Active Notch3 induced expression of PDGFRB2, N-Cadherin , HBEGF , TGFB1, NG2 , and S1P genes. Notch3 signaling in pericytes enhanced the adhesion strength of pericytes to endothelial cells, limited their migratory and invasive behavior, and enhanced their antiangiogenic function. Pericytes silenced for Notch3 expression were more motile and could not efficiently repress angiogenesis. Conclusions— The data suggest that Notch signaling in pericytes is important to maintain the quiescent vascular phenotype. Deregulated Notch signaling may, therefore, contribute to the pathogenesis of CCM.

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Expression of platelet-derived growth factor ligand and receptor in cerebral arteriovenous and cavernous malformations

Cited by 22 publications

References 32 publications

De novo cerebral arteriovenous malformation in a child with previous cavernous malformation and developmental venous anomaly

De novo cerebral arteriovenous malformation in a child with previous cavernous malformation and developmental venous anomaly

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes

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