Clinical progression and familial occurrence of cerebral cavernous angiomas: the role of angiogenic and growth factors

Maiuri, Francesco; Cappabianca, Paolo; Gangemi, M; De, Marialaura Del Basso; Esposito, Felice; Pettinato, Guido; Divitiis, Oreste de; Mignogna, Chiara; Strazzullo, Viviana; Divitiis, Enrico de

doi:10.3171/foc.2006.21.1.4

Cited by 47 publications

(34 citation statements)

References 47 publications

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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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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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“…The detection of high plasma TGF-β1 and VEGF levels may support the diagnosis of cavernous angioma (16), and TGF-β1 and VEGF regulate angiogenesis. In addition, previous studies have shown that TGF-β1 and VEGF are overexpressed in cavernous angiomas (17,18). However, the association between TGF-β1 and the disease activity was unclear in this case.…”

Section: Discussionmentioning

confidence: 61%

Medullary Hemorrhage that Preceded the Onset of Multiple Cavernous Angiomas

Naoi¹,

Nakao

Nakamura³

et al. 2015

Intern. Med.

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Medullary hemorrhage is rare, and the causative role of hypertension still remains controversial. Cavernous angioma and other vascular malformations have been reported to cause medullary hemorrhage. A 53-year-old man was admitted to our hospital for vertigo. Medullary hemorrhage and multiple small hypointense lesions were detected on T2-star weighted magnetic resonance imaging (T2*W MRI). One and four months later, the appearance of new lesions confirmed the diagnosis of cerebral cavernous angioma. Cavernous angioma is often characterized by de novo appearance/progression on MRI. A follow-up MRI is required to diagnose cavernous angioma in patients with medullary hemorrhage.

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“…Factors influencing the onset of cavernomas are still unknown. Genetic alterations may be involved in the familial form (14). On the other hand, in the sporadic variant, cavernomas could result from the evolution of small unpredictable lesions following hemorrhages or capillary proliferation (20).…”

Section: Discussionmentioning

confidence: 99%

Multiple cavernomas of the brain: simultaneous hemorrhage of two lesions in a non-familial form

Panciani

Agnoletti²,

Fornaro³

et al. 2011

Turkish Neurosurgery

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BackgrOund: Cavernomas of the brain are congenital lesions clinically divided into hereditary and a sporadic forms. Multiple lesions are usually observed in the familial form, whereas the sporadic variant generally shows a single cavernoma. In this case we describe the simultaneous bleeding of two lesions in a patient with a non-familial cavernomatosis.case descrIptIOn: A 46-year-old woman presented with slight hyposthenia involving the left arm and cervical stiffness. Examinations revealed two cavernomas with recent signs of bleeding. The lesions were surgically removed achieving a total excision. The patient was discharged after 10 days with slight left hyposthenia.dIscussIOn: Simultaneous hemorrhage of multiple cavernomas is rare. To the best of our knowledge, this is the first case showing a sporadic form presenting with two hemorrhagic lesions. We suggest an aggressive approach in order to avoid the risk of rebleeding, which is particularly high in case of hemorrhagic cavernomatosis.keywOrds: Hemangioma, Cavernous, Central nervous system, Hemorrhage, Familial cerebral cavernous malformation ÖZ aMaÇ: Beyin kavernomları klinik olarak herediter ve sporadik forma bölünen konjenital lezyonlardır. Multipl lezyonlar genellikle ailesel formda görülürken, sporadik varyantta genelde tek kavernom görülür. Bu olguda ailesel olmayan kavernomatosisi olan bir hastada iki lezyonda eş zamanlı kanama tanımlıyoruz.OLgu sunuMu: 46 yaşında bir kadın sol kolda hafif hiposteni ve servikal sertlikle geldi. Muayeneler yakın zamanlı kanama bulgularıyla iki kavernom gösterdi. Lezyonlar cerrahi olarak çıkarılıp tam eksizyon elde edildi. Hasta 10 gün sonra hafif bir sol hiposteniyle taburcu edildi. tartIşMa: Multipl kavernomların eş zamanlı kanaması nadirdir. Bildiğimiz kadarıyla bu hasta iki hemorajik lezyonla gelen ilk sporadik form olgusudur. Özellikle hemorajik kavernomatoz olgularında yüksek olan tekrar kanama riskinden kaçınmak için agresif bir yaklaşım öneriyoruz.anaHtar sÖZcÜkLer: Hemanjiyom, Kavernöz, Merkez sinir sistemi, Kanama, Ailesel serebral kavernöz malformasyon

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Clinical progression and familial occurrence of cerebral cavernous angiomas: the role of angiogenic and growth factors

Cited by 47 publications

References 47 publications

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

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

Medullary Hemorrhage that Preceded the Onset of Multiple Cavernous Angiomas

Multiple cavernomas of the brain: simultaneous hemorrhage of two lesions in a non-familial form

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