title: BMP signaling modulation attenuates cerebral arteriovenous malformation formation in a vertebrate model.
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.
authors: 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.
authors: Brian P
authors: BP
authors: Walcott
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001165:Arteriovenous Malformations / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002536:Cerebral Arteries / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002550:Cerebral Veins / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D019808:Losartan / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D051898:Smad1 Protein / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; D029961:Zebrafish Proteins; D030201:Activin Receptors, Type I; D019808:Losartan