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VEGF Induces More Severe Cerebrovascular Dysplasia in Endoglin than in Alk1 Mice.

Hao Q, Zhu Y, Su H, Shen F, Yang GY, Kim H, Young WL - Transl Stroke Res (2010)

Bottom Line: The BAVM phenotype is an incomplete penetrant in HHT patients, and the mechanism is unknown.Adeno-associated virus (AAV) expressing vascular endothelial growth factor (VEGF) was used to mimic the injury conditions.Our data indicate that both angiogenic stimulation and genetic alteration are necessary for the development of dysplasia, suggesting that anti-angiogenic therapies might be adapted to slow the progression of the disease and decrease the risk of spontaneous ICH.

View Article: PubMed Central - PubMed

Affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue Room 3C-38, San Francisco, CA 94110, USA.

ABSTRACT
Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. A small percent of BAVMs is due to hereditary hemorrhagic telangiectasia 1 and 2 (HHT1 and 2), which are caused by mutations in two genes involved in TGF-β signaling: endoglin (ENG) and activin-like kinase 1 (ALK1). The BAVM phenotype is an incomplete penetrant in HHT patients, and the mechanism is unknown. We tested the hypothesis that a "response-to-injury" triggers abnormal vascular (dysplasia) development, using Eng and Alk1 haploinsufficient mice. Adeno-associated virus (AAV) expressing vascular endothelial growth factor (VEGF) was used to mimic the injury conditions. VEGF overexpression caused a similar degree of angiogenesis in the brain of all groups, except that the cortex of Alk1(+/-) mice had a 33% higher capillary density than other groups. There were different levels of cerebrovascular dysplasia in haploinsufficient mice (Eng(+/)>Alk1(+/-)), which simulates the relative penetrance of BAVM in HHT patients (HHT1>HHT2). Few dysplastic capillaries were observed in AAV-LacZ-injected mice. Our data indicate that both angiogenic stimulation and genetic alteration are necessary for the development of dysplasia, suggesting that anti-angiogenic therapies might be adapted to slow the progression of the disease and decrease the risk of spontaneous ICH.

No MeSH data available.


Related in: MedlinePlus

In the cortex. A Injection site (gray square). B Angiogenic foci and dysplastic capillaries (arrows). Inserts are enlarged images of dysplastic capillaries. Scale bars are 100 (top panel) and 50 µm (bottom panel). C, D The capillary density and dysplasia index. Asterisk (in C), p < 0.05 vs. AAV-LacZ group. Asterisk (in D), p < 0.05 vs. AAV-VEGF-transduced WT. Number sign, p < 0.05 vs. AAV-VEGF-transduced Alk1+/− mice. VEGF: AAV-VEGF-injected mice, LacZ: AAV-LacZ-injected mice. N = 3
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Fig2: In the cortex. A Injection site (gray square). B Angiogenic foci and dysplastic capillaries (arrows). Inserts are enlarged images of dysplastic capillaries. Scale bars are 100 (top panel) and 50 µm (bottom panel). C, D The capillary density and dysplasia index. Asterisk (in C), p < 0.05 vs. AAV-LacZ group. Asterisk (in D), p < 0.05 vs. AAV-VEGF-transduced WT. Number sign, p < 0.05 vs. AAV-VEGF-transduced Alk1+/− mice. VEGF: AAV-VEGF-injected mice, LacZ: AAV-LacZ-injected mice. N = 3

Mentions: In the cortex, CD was similar in all groups, except that Alk1+/− mice (342 ± 76) had a 33% higher CD than Eng/Alk1+/− (258 ± 56) and Eng+/− (259 ± 46) mice (P < 0.05). Vascular dysplasia was also similar to that seen in the striatum, but differences among groups were less marked. The dysplasia index was higher in Eng+/− mice (2.3 ± 1.2) than in Alk1+/− (1.2 ± 0.8) (P < 0.05; Fig. 2).Fig. 2


VEGF Induces More Severe Cerebrovascular Dysplasia in Endoglin than in Alk1 Mice.

Hao Q, Zhu Y, Su H, Shen F, Yang GY, Kim H, Young WL - Transl Stroke Res (2010)

In the cortex. A Injection site (gray square). B Angiogenic foci and dysplastic capillaries (arrows). Inserts are enlarged images of dysplastic capillaries. Scale bars are 100 (top panel) and 50 µm (bottom panel). C, D The capillary density and dysplasia index. Asterisk (in C), p < 0.05 vs. AAV-LacZ group. Asterisk (in D), p < 0.05 vs. AAV-VEGF-transduced WT. Number sign, p < 0.05 vs. AAV-VEGF-transduced Alk1+/− mice. VEGF: AAV-VEGF-injected mice, LacZ: AAV-LacZ-injected mice. N = 3
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Related In: Results  -  Collection

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Fig2: In the cortex. A Injection site (gray square). B Angiogenic foci and dysplastic capillaries (arrows). Inserts are enlarged images of dysplastic capillaries. Scale bars are 100 (top panel) and 50 µm (bottom panel). C, D The capillary density and dysplasia index. Asterisk (in C), p < 0.05 vs. AAV-LacZ group. Asterisk (in D), p < 0.05 vs. AAV-VEGF-transduced WT. Number sign, p < 0.05 vs. AAV-VEGF-transduced Alk1+/− mice. VEGF: AAV-VEGF-injected mice, LacZ: AAV-LacZ-injected mice. N = 3
Mentions: In the cortex, CD was similar in all groups, except that Alk1+/− mice (342 ± 76) had a 33% higher CD than Eng/Alk1+/− (258 ± 56) and Eng+/− (259 ± 46) mice (P < 0.05). Vascular dysplasia was also similar to that seen in the striatum, but differences among groups were less marked. The dysplasia index was higher in Eng+/− mice (2.3 ± 1.2) than in Alk1+/− (1.2 ± 0.8) (P < 0.05; Fig. 2).Fig. 2

Bottom Line: The BAVM phenotype is an incomplete penetrant in HHT patients, and the mechanism is unknown.Adeno-associated virus (AAV) expressing vascular endothelial growth factor (VEGF) was used to mimic the injury conditions.Our data indicate that both angiogenic stimulation and genetic alteration are necessary for the development of dysplasia, suggesting that anti-angiogenic therapies might be adapted to slow the progression of the disease and decrease the risk of spontaneous ICH.

View Article: PubMed Central - PubMed

Affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue Room 3C-38, San Francisco, CA 94110, USA.

ABSTRACT
Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. A small percent of BAVMs is due to hereditary hemorrhagic telangiectasia 1 and 2 (HHT1 and 2), which are caused by mutations in two genes involved in TGF-β signaling: endoglin (ENG) and activin-like kinase 1 (ALK1). The BAVM phenotype is an incomplete penetrant in HHT patients, and the mechanism is unknown. We tested the hypothesis that a "response-to-injury" triggers abnormal vascular (dysplasia) development, using Eng and Alk1 haploinsufficient mice. Adeno-associated virus (AAV) expressing vascular endothelial growth factor (VEGF) was used to mimic the injury conditions. VEGF overexpression caused a similar degree of angiogenesis in the brain of all groups, except that the cortex of Alk1(+/-) mice had a 33% higher capillary density than other groups. There were different levels of cerebrovascular dysplasia in haploinsufficient mice (Eng(+/)>Alk1(+/-)), which simulates the relative penetrance of BAVM in HHT patients (HHT1>HHT2). Few dysplastic capillaries were observed in AAV-LacZ-injected mice. Our data indicate that both angiogenic stimulation and genetic alteration are necessary for the development of dysplasia, suggesting that anti-angiogenic therapies might be adapted to slow the progression of the disease and decrease the risk of spontaneous ICH.

No MeSH data available.


Related in: MedlinePlus