PMID:19855400

Citation	Li, X, Zhang, X, Leathers, R, Makino, A, Huang, C, Parsa, P, Macias, J, Yuan, JX, Jamieson, SW and Thistlethwaite, PA (2009) Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15:1289-97
Abstract	Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3-HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention.
Links	PubMed PMC2780347 Online version:10.1038/nm.2021
Keywords	Animals; Anoxia/drug therapy; Anoxia/physiopathology; Basic Helix-Loop-Helix Transcription Factors/metabolism; Cell Proliferation/drug effects; Dipeptides/pharmacology; Dipeptides/therapeutic use; Disease Models, Animal; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/therapeutic use; Gene Expression Regulation/drug effects; Gene Expression Regulation/physiology; Humans; Hypertension, Pulmonary/drug therapy; Hypertension, Pulmonary/metabolism; Hypertension, Pulmonary/pathology; Lung/metabolism; Lung/pathology; Mice; Mice, Knockout; Microscopy, Electron, Transmission/methods; Myocytes, Smooth Muscle; Pulmonary Artery/metabolism; Pulmonary Artery/pathology; Pulmonary Artery/physiopathology; Pulmonary Artery/ultrastructure; RNA, Messenger/metabolism; Rats; Receptors, Notch/deficiency; Receptors, Notch/metabolism; Repressor Proteins/metabolism; Signal Transduction/drug effects; Signal Transduction/genetics; Signal Transduction/physiology; Time Factors
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HES5	involved_in	GO:0048661: positive regulation of smooth muscle cell proliferation	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:Q61982	P		Seeded From UniProt	complete
HUMAN:HES5	involved_in	GO:0007219: Notch signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:NOTC3	involved_in	GO:0007219: Notch signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:NOTC3	involved_in	GO:0048661: positive regulation of smooth muscle cell proliferation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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