Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression

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dc.contributor.authorSachdeva, Jaspreeten_ZA
dc.contributor.authorMahajan, Advitiyaen_ZA
dc.contributor.authorCheng, Jeeyunen_ZA
dc.contributor.authorBaeten, Jeremy T.en_ZA
dc.contributor.authorLilly, Brendaen_ZA
dc.contributor.authorKuivaniemi, Helenaen_ZA
dc.contributor.authorHans, Chetan P.en_ZA
dc.date.accessioned2019-02-26T09:16:07Z
dc.date.available2019-02-26T09:16:07Z
dc.date.issued2017
dc.descriptionCITATION: Sachdeva, J., et al. 2017. Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression. PLoS ONE, 12(5):e0178538, doi:10.1371/journal.pone.0178538.
dc.descriptionThe original publication is available at https://journals.plos.org/plosone
dc.description.abstractAims: Infiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development. Methods and results: Cell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF. Conclusions: Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.en_ZA
dc.description.urihttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178538
dc.description.versionPublisher's version
dc.format.extent25 pages
dc.identifier.citationSachdeva, J., et al. 2017. Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression. PLoS ONE, 12(5):e0178538, doi:10.1371/journal.pone.0178538
dc.identifier.issn1932-6203 (online)
dc.identifier.otherdoi:10.1371/journal.pone.0178538
dc.identifier.urihttp://hdl.handle.net/10019.1/105474
dc.language.isoen_ZAen_ZA
dc.publisherPublic Library of Science
dc.rights.holderAuthors retain copyright
dc.subjectSmooth muscle cellsen_ZA
dc.subjectAbdominal aorta -- Diseasesen_ZA
dc.subjectAortic aneurysms -- Preventionen_ZA
dc.subjectAneurysms -- Preventionen_ZA
dc.subjectNotch1 haploinsufficiencyen_ZA
dc.subjectVascular smooth muscleen_ZA
dc.titleSmooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expressionen_ZA
dc.typeArticleen_ZA
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