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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1502-1510.
Prepublished online as a Blood First Edition Paper on May 11, 2007; DOI 10.1182/blood-2006-11-058594.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity
Dong Liu1,
Jian Wang1,
Bernd Kinzel2,
Matthias Müeller2,
Xiaohong Mao1,
Reginald Valdez1,
Yongxing Liu1, and
En Li3
1 Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA;
2 Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland; and
3 Models of Disease Center, Novartis Institutes for Biomedical Research, Cambridge, MA
Germ-line mutations in bone morphogenic protein type II receptor (Bmpr2) confer susceptibility to pulmonary arterial hypertension (PAH), which is characterized by obstructive vascular lesions in small arteries. The molecular and cellular mechanisms that account for the etiology of this disorder remain elusive, as does the role of Bmpr2 in postnatal tissue homeostasis. Here we show that in adult mice, stably silencing Bmpr2 expression by RNA interference does not increase pulmonary arterial resistance but results in severe mucosal hemorrhage, incomplete mural cell coverage on vessel walls, and gastrointestinal hyperplasia. We present evidence that BMP receptor signaling regulates vascular remodeling during angiogenesis by maintaining the expression of endothelial guidance molecules that promote vessel patterning and maturation and by counteracting growth factor–induced AKT activation. Attenuation of this function may cause vascular dysmorphogenesis and predisposition to angioproliferative diseases. Our findings provide a mechanistic link between PAH and other diseases associated with the BMP/TGF-ß pathways, such as hereditary hemorrhagic telangiectasia and juvenile polyposis syndrome.
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