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

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...

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Bibliographic Details
Published in:PloS one 2017-05, Vol.12 (5), p.e0178538-e0178538
Main Authors: Sachdeva, Jaspreet, Mahajan, Advitiya, Cheng, Jeeyun, Baeten, Jeremy T, Lilly, Brenda, Kuivaniemi, Helena, Hans, Chetan P
Format: Article
Language:English
Subjects:
Abdomen
Abdominal aortic aneurysm
Analysis
Aneurysms
Angiotensin
Angiotensin II
Angiotensins
Animals
Aorta
Aortic Aneurysm, Abdominal - metabolism
Aortic Aneurysm, Abdominal - pathology
Aortic aneurysms
Apolipoprotein E
Apoptosis
Biology and Life Sciences
Cardiology
Cell culture
Cells, Cultured
Children & youth
Coculture Techniques
Connective tissue growth factor
Connective Tissue Growth Factor - metabolism
Connective tissues
Coronary vessels
Degradation
Development and progression
Dilation
Elastin
Growth factors
Haploinsufficiency
Health aspects
Heart
Hospitals
In vitro methods and tests
Infiltration
Intracellular
Liquid oxygen
Macrophages
Markers
Matrix Metalloproteinases - biosynthesis
Medicine
Medicine and Health Sciences
Mice
Muscle contraction
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - enzymology
Muscle, Smooth, Vascular - metabolism
Myeloid cells
Notch1 protein
Phenotypes
Physiology
Proteins
Receptor, Notch1 - metabolism
Research and Analysis Methods
Rodents
siRNA
Smooth muscle
Surgery
Technology
Technology utilization
Tissue engineering
Transplants & implants
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Description
Summary: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. 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. Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0178538