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Aims  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.

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