9/6/2014 1 CCR UCSF center for cerebrovascular research Brain AVM Models and Novel Therapeutic Targets 2 nd UCSF Stroke and Aneurysm Update CME Saturday September 6, 2014 Hua Su, MD. Professor Center for Cerebrovascular Research Department of Anesthesia and Perioperative Care University of California, San Francisco [email protected]CCR UCSF center for cerebrovascular research I have nothing to disclose. CCR UCSF center for cerebrovascular research Brain Arteriovenous Malformations (AVMs) •Tangle of abnormal blood vessels (nidus) –Arteriovenous shunting –No intranidal capillary bed –Range of vessel types • Located randomly throughout brain • Cause of hemorrhagic stroke CCR UCSF center for cerebrovascular research Current Treatments Surgery, embolization and radiosurgery No specific medical therapy for brain AVM Death or Stoke (%) Months Invasive therapy (n=114) HR=0.27 (95% CI: 0.14-0.54) Medical management (n=109) The goals of specific medical treatments are: 1. Stabilize vessel wall -reduce spontaneous intracranial hemorrhage and hemorrhagic stroke 2. Reduce brain AVM grow or regrow after invasive treatment 3. Reduce AVM volume -surgical resection easier -reduce risk of invasive procedures
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Brain AVM Models and Novel Therapeutic Targets · Novel Therapeutic Targets 2nd UCSF Stroke and Aneurysm Update CME Saturday September 6, 2014 Hua Su, MD. Professor Center for Cerebrovascular
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9/6/2014
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CCR UCSF center for cerebrovascular research
Brain AVM Models and Novel Therapeutic Targets
2nd UCSF Stroke and Aneurysm Update CMESaturday September 6, 2014
Hua Su, MD. Professor
Center for Cerebrovascular ResearchDepartment of Anesthesia and Perioperative Care
Corrosion casting and SEM revealed AVMs in 3/10 mice
Srinivasan, et al, Hum Mol Genet 12: 473, 2003
In >47 mice, one Alk1+/- with dilated cerebellar vessel
CCR UCSF center for cerebrovascular research
AdCre – Regional Conditional Deletion of Alk1
loxp
loxp
CMV Promoter Cre recombinase
Promoter
Promoter
loxp
AdCre
Exons 4, 5, 6Exo
n 3
Exo
n 7
Exo
n 3
Alk 1 gene
Exons 4,5,6 are deleted from Alk1 genome
Exo
n 7
CCR UCSF center for cerebrovascular research
Alk1 Regional Conditional Deletion Plus VEGF Stimulation Results in Brain AVM
AdCre + AAV-VEGF
8 wks
Alk1 -/-
Angiogenesis
Walker et al. Ann Neurology, 2011 CCR UCSF center for cerebrovascular research
Alk1+/+/VEGF
Alk1-/- onlyAlk1-/- /VEGF
VEGF Stimulation is Necessary for Brain AVM Formation
Alk1+/+/VEGF
Walker et al. Ann Neurology, 2011
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CCR UCSF center for cerebrovascular research
Chen et al. Translational Stroke Research, 2014
Adult onset AVM models
Choi et al., PLOS One, 2014
CCR UCSF center for cerebrovascular researchChen et al, Stroke, 2014
Some Models have AVM in Other Organs
skin
CCR UCSF center for cerebrovascular research
Macrophage Infiltration
Chen et al. ATVB, 2013 CCR UCSF center for cerebrovascular research
AVM vessels have less smooth muscle cell coverage
Chen et al. ATVB, 2013
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CCR UCSF center for cerebrovascular research
AVM vessels have less pericyte coverage
Chen et al. ATVB, 2013 CCR UCSF center for cerebrovascular research
Microhemorrhage
Chen et al. ATVB, 2013
CCR UCSF center for cerebrovascular research
ALK1 Knockdown Attenuates the Upregulation of PDGFB in HBMEC in Response to VEGF Stimulation
HBMEC (human brain microvascular endothelial cell) were transfected with control shRNA or shRNA . Cells with >70% reduction of Alk1 gene expression were cultured for 18 h in the presence or absence of VEGF (0, 10, 50, and 100 ng/ml). qRT-PCR was performed for Alk1(A) and Pdgfb (B). All data are shown as mean and SD. *p<0.05 vs. control.
B
0
1
2
3
4
5
Pd
gfb
mR
NA
Fol
d C
hang
e
ControlshAlk1
VEGF 0 10 50 100(ng /ml)
**
*
0
0.5
1
1.5
2
2.5
3
Alk
1m
RN
A F
old
Cha
nge
ControlshAlk1
A
VEGF 0 10 50 100(ng /ml)
* * * *
CCR UCSF center for cerebrovascular research
ALK1 knockdown in HBMEC impairs the pericyte recruitment
20 40 60
VEGF + shAlk1
shAlk1
VEGF
Control
Average Pericyte Distance µm
A B
**
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CCR UCSF center for cerebrovascular research
50 µm
Gene Mutation in Bone Marrow Transmits the Phenotype
CCR UCSF center for cerebrovascular research
Reduction of Gene Mutant Endothelial Cell Reduced GI Hemorrhage and Mortality
1. Invasive therapies are associated with considerable risks2. No specific medical therapy is available3. The concept for the treatment of brain AVM is to
stabilize vascular tissue and thereby decrease the risk of spontaneous ICH.
4. Novel therapeutic approaches: A. Anti-inflammationB. Anti-angiogenesisC. Improve vascular integrityD. Correct gene mutation in BM monocyte/progenitors
CCR UCSF center for cerebrovascular research
Thank You
William L. Young Mervyn MazeHelen KimLudmila PawlikowskaMichael T. LawtonCharles E. McCulloch