NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response.

NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Research Abstract Details 

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NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Abstract Text:

Junwang Xu,Fraz A Ismat,Tao Wang,Jifu Yang,Jonathan A Epstein,Junwang Xu,Fraz A Ismat,Tao Wang,Jifu Yang,Jonathan A Epstein,

BACKGROUND: Neurofibromatosis type I (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, osseous dysplasias, and characteristic cutaneous findings. In addition, NF1 patients have an increased incidence of cardiovascular diseases, including obstructive vascular disorders. In animal models, endothelial expression of the disease gene, NF1, is critical for normal heart development. However, the pathogeneses of the more common vascular disorders are not well characterized. METHODS AND RESULTS: To examine the role of NF1 in vascular smooth muscle, we generated mice with homozygous loss of the murine homolog Nf1 in smooth muscle (Nf1smKO). These mice develop and breed normally. However, in response to vascular injury, they display a marked intimal hyperproliferation and abnormal activation of mitogen-activated protein kinase, a downstream effector of Ras. Vascular smooth muscle cells cultured from these mice also display enhanced proliferation and mitogen-activated protein kinase activity. Smooth muscle expression of the NF1 Ras-regulatory domain (GTPase activating protein-related domain) rescues intimal hyperplasia in Nf1smKO mice and normalizes vascular smooth muscle cell Ras effector activity and proliferation in vitro, similar to blockade of downstream effectors of Ras. CONCLUSIONS: In this in vivo model of NF1 obstructive vascular disease, we have shown that Nf1 regulation of Ras plays a critical role in vascular smooth muscle proliferation after injury. These results suggest opportunities for targeted therapeutics in the prevention and treatment of NF1-related vascular disease and in the treatment of neointimal proliferation in other settings.

NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Publishing Authors By Initials

J Xu,FA Ismat,T Wang,J Yang,JA Epstein,J Xu,FA Ismat,T Wang,J Yang,JA Epstein,

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NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Circulation

VOLUME: 116

Page Numbers: 2148-56

Journal Abbreviation: Circulation

ISSN: 1524-4539

DAY: 22

MONTH: 10

YEAR: 2007

NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Information

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LANGUAGE: eng

NlmUniqueID: 147763

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Grant and Affiliation Information for NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response.

AFFILIATION: Department of Cell and Developmental Biology and Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R01 HL62974

ACRONYM: HL

MEDLINETA: Circulation

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