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Advances in the biology of cerebral cavernous malformations.

Hauptman JS, Moftakhar P, Dadour A, Malkasian D, Martin NA - Surg Neurol Int (2010)

Bottom Line: In vivo work suggests the likelihood of a "two-hit mechanism" resulting in somatic mosaicism and biallelic loss of angiogenic genes.The etiological effects of angioarchitecture and immune response within these lesions further complicate the pathophysiology.Future treatment endeavors will necessitate exploitation of the multiple facets of CCM formation to maximize success at CCM prevention or obliteration.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles, USA.

ABSTRACT

Object: To provide a review of current, high-impact scientific findings pertaining to the biology of cerebral cavernous malformations (CCMs).

Methods: A comprehensive literature review was conducted using PubMed to examine the current literature regarding the molecular biology and pathophysiology of CCMs.

Results: In this literature review, a comprehensive approach is taken to review the current scientific status of CCMs. This includes discussion of molecular biology and animal models, ultrastructure and angioarchitectural features and immunological methods and hypotheses.

Conclusions: Studies examining the molecular biology of CCMs have shown that genes involved in angiogenesis, blood-brain barrier formation, cell size regulation, vascular permeability and apoptosis play critical roles in the ontogeny of this disease. In vivo work suggests the likelihood of a "two-hit mechanism" resulting in somatic mosaicism and biallelic loss of angiogenic genes. The etiological effects of angioarchitecture and immune response within these lesions further complicate the pathophysiology. Future treatment endeavors will necessitate exploitation of the multiple facets of CCM formation to maximize success at CCM prevention or obliteration.

No MeSH data available.


Related in: MedlinePlus

Schematic of the role of Krit-1/CCM1 in angiogenesis. Krit-1/CCM-1 interacts with integrins that in turn facilitate the pro-angiogenic cascade. This includes activation of pathways involved in protein synthesis, proliferation, and adhesion
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Figure 0001: Schematic of the role of Krit-1/CCM1 in angiogenesis. Krit-1/CCM-1 interacts with integrins that in turn facilitate the pro-angiogenic cascade. This includes activation of pathways involved in protein synthesis, proliferation, and adhesion

Mentions: Krit1 (Krev-1 interaction trapped 1)/CCM1 is located on chromosome 7q21.[102049] Krit1/CCM1 was initially identified as a putative tumor-suppressor gene, endogenously expressed at low levels and acting to inhibit Ras activation through an interaction with Krev-1 (Kirsten-ras-revertant 1).[2749] Krev-1 is though to antagonize cell growth in response to G-protein activation from negative growth-regulatory signals.[26] Krit1/CCM1 encodes a microtubule-associated protein that likely directs cytoskeletal structure and helps to determine endothelial cell size, shape and function.[19] Krit1 also plays a role in cell–cell adhesion, possibly explaining the enhanced permeability of CCMs and propensity for hemorrhage.[62] This is likely integrin dependent, with work demonstrating Krit1/CCM1’s function in beta1 integrin-dependent angiogenesis [Figure 1].[3563] Immunostaining for Krit1/CCM1 in multiple organs has revealed positivity in the endothelium of capillaries and arterioles, particularly in areas where a blood-organ barrier exists.[20] In the brain, expression of Krit1/CCM1 is found within astrocytic foot processes and cortical pyramidal neurons in addition to the vascular endothelium, suggesting a role in angiogenesis and blood-brain barrier formation.


Advances in the biology of cerebral cavernous malformations.

Hauptman JS, Moftakhar P, Dadour A, Malkasian D, Martin NA - Surg Neurol Int (2010)

Schematic of the role of Krit-1/CCM1 in angiogenesis. Krit-1/CCM-1 interacts with integrins that in turn facilitate the pro-angiogenic cascade. This includes activation of pathways involved in protein synthesis, proliferation, and adhesion
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2958334&req=5

Figure 0001: Schematic of the role of Krit-1/CCM1 in angiogenesis. Krit-1/CCM-1 interacts with integrins that in turn facilitate the pro-angiogenic cascade. This includes activation of pathways involved in protein synthesis, proliferation, and adhesion
Mentions: Krit1 (Krev-1 interaction trapped 1)/CCM1 is located on chromosome 7q21.[102049] Krit1/CCM1 was initially identified as a putative tumor-suppressor gene, endogenously expressed at low levels and acting to inhibit Ras activation through an interaction with Krev-1 (Kirsten-ras-revertant 1).[2749] Krev-1 is though to antagonize cell growth in response to G-protein activation from negative growth-regulatory signals.[26] Krit1/CCM1 encodes a microtubule-associated protein that likely directs cytoskeletal structure and helps to determine endothelial cell size, shape and function.[19] Krit1 also plays a role in cell–cell adhesion, possibly explaining the enhanced permeability of CCMs and propensity for hemorrhage.[62] This is likely integrin dependent, with work demonstrating Krit1/CCM1’s function in beta1 integrin-dependent angiogenesis [Figure 1].[3563] Immunostaining for Krit1/CCM1 in multiple organs has revealed positivity in the endothelium of capillaries and arterioles, particularly in areas where a blood-organ barrier exists.[20] In the brain, expression of Krit1/CCM1 is found within astrocytic foot processes and cortical pyramidal neurons in addition to the vascular endothelium, suggesting a role in angiogenesis and blood-brain barrier formation.

Bottom Line: In vivo work suggests the likelihood of a "two-hit mechanism" resulting in somatic mosaicism and biallelic loss of angiogenic genes.The etiological effects of angioarchitecture and immune response within these lesions further complicate the pathophysiology.Future treatment endeavors will necessitate exploitation of the multiple facets of CCM formation to maximize success at CCM prevention or obliteration.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles, USA.

ABSTRACT

Object: To provide a review of current, high-impact scientific findings pertaining to the biology of cerebral cavernous malformations (CCMs).

Methods: A comprehensive literature review was conducted using PubMed to examine the current literature regarding the molecular biology and pathophysiology of CCMs.

Results: In this literature review, a comprehensive approach is taken to review the current scientific status of CCMs. This includes discussion of molecular biology and animal models, ultrastructure and angioarchitectural features and immunological methods and hypotheses.

Conclusions: Studies examining the molecular biology of CCMs have shown that genes involved in angiogenesis, blood-brain barrier formation, cell size regulation, vascular permeability and apoptosis play critical roles in the ontogeny of this disease. In vivo work suggests the likelihood of a "two-hit mechanism" resulting in somatic mosaicism and biallelic loss of angiogenic genes. The etiological effects of angioarchitecture and immune response within these lesions further complicate the pathophysiology. Future treatment endeavors will necessitate exploitation of the multiple facets of CCM formation to maximize success at CCM prevention or obliteration.

No MeSH data available.


Related in: MedlinePlus