Format

Send to

Choose Destination
J Cereb Blood Flow Metab. 2014 Oct;34(10):1688-94. doi: 10.1038/jcbfm.2014.134. Epub 2014 Jul 23.

BMP signaling modulation attenuates cerebral arteriovenous malformation formation in a vertebrate model.

Author information

1
1] Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA [2] Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.

Abstract

Cerebral arteriovenous malformations (AVMs) are vascular anomalies that carry a high risk of stroke and death. To test potential AVM therapies, a reverse genetics approach was used to model AVMs in zebrafish. Antisense morpholino oligonucleotides were used to knockdown activin receptor-like kinase I (alk1), which encodes a transforming growth factor (TGF)-beta family type I receptor implicated in a subset of human AVMs. Knockdown of alk1 caused a spectrum of morphologic, functional, and molecular defects that resemble those seen in humans with AVMs. It was found that losartan, an angiotensin II receptor antagonist, attenuated abnormal blood vessel morphology and systemic manifestations of high-output arteriovenous shunting in vivo. SMAD1 phosphorylation was significantly decreased in alk1 morphants compared with uninjected organisms (0.189±0.0201, 0.429±0.0164, P=0.0002). After treatment, morphant SMAD1 levels approached uninjected levels (0.326±0.0360, P=0.0355) and were significantly higher than those seen in the morphant-control group (P=0.0294). These data suggest that modulating the BMP signaling pathway with losartan, a drug in widespread clinical use in humans as an antihypertensive, may have the potential to be further evaluated as a therapeutic strategy for patients with AVMs.

PMID:
25052553
PMCID:
PMC4269730
DOI:
10.1038/jcbfm.2014.134
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center