Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease

Bosse, Kevin; Hans, Chetan P.; Zhao, Ning; Koenig, Sara N.; Huang, Nianyuan; Guggilam, Anuradha; LaHaye, Stephanie; Tao, Ge; Lucchesi, Pamela A.; Lincoln, Joy; Lilly, Brenda; Garg, Vidu

doi:10.1016/j.yjmcc.2013.04.001

Cited by 152 publications

(173 citation statements)

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“…Nos3 −/− and Notch1 +/− ;Nos3 +/− mice were bred to obtain Notch1 +/− ;Nos3 −/− mice (n=49) and littermate controls (n=216) and were genotyped, as described previously 20. For lineage‐specific deletions of Notch1 (using Tie2‐Cre,21 Mef2C‐Cre,22 Wnt1‐Cre23), Nos3 −/− ;Cre +/− male mice were bred with Notch1 flox/wt ;Nos3 +/− female mice to obtain Notch1 flox/wt ;Tie2‐Cre +/− ;Nos3 −/− (n=6) mice, Notch1 flox/wt ;Mef2C‐Cre +/− ;Nos3 −/− (n=7), Notch1 flox/wt ;Wnt1‐Cre +/− ;Nos3 −/− (n=4), and control littermates (n=4, n=4, n=4, respectively).…”

Section: Methodsmentioning

confidence: 99%

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Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

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BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.

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Section: Methodsmentioning

confidence: 99%

“…We previously described reduced survival to adulthood in Notch1 +/− ;Nos3 −/− mice, suggesting a potential embryonic phenotype 20. To further investigate the cause of this lethality, we bred Notch1 +/− ;Nos3 +/− female mice with Nos3 −/− male mice and examined the resultant litters.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

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“…13 NOTCH is the expected ligand for the DLL4 receptor, and there is a reported role for NOTCH signaling in VEC-VEC signaling, VIC-induced calcification, and valvulogenesis. 5,30 However, it is unclear if the same downstream pathways previously related to calcification and NOTCH are at play in this model. Further studies are needed to examine whether sustained angiogenic signaling leads towards valve calcification through angiogenetic-related cell-cell contact NOTCH inhibition.…”

Section: Discussionmentioning

confidence: 91%

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

et al. 2016

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Neovascularization is an understudied aspect of calcific aortic valve disease (CAVD). Within diseased valves, cells along the neovessels' periphery stain for pericyte markers, but it is unclear whether valvular interstitial cells (VICs) can demonstrate a pericyte-like phenotype. This investigation examined the perivascular potential of VICs to regulate valve endothelial cell (VEC) organization and explored the role of Angiopoeitin1-Tie2 signaling in this process. Porcine VECs and VICs were fluorescently tracked and co-cultured in Matrigel over 7 days. VICs regulated early VEC network organization in a ROCK-dependent manner, then guided later VEC network contraction through chemoattraction. Unlike vascular control cells, the valve cell cultures ultimately formed invasive spheroids with 3D angiogenic-like sprouts. VECs co-cultured with VICs displayed significantly more invasion than VECs alone; with VICs generally leading and wrapping around VEC invasive sprouts. Lastly, Angiopoietin1-Tie2 signaling was found to regulate valve cell organization during VEC/VIC spheroid formation and invasion. VICs demonstrated pericyte-like behaviors toward VECs throughout sustained co-culture. The change from a vasculogenic network to an invasive sprouting spheroid suggests that both cell types undergo phenotypic changes during long-term culture in the model angiogenic environment. Valve cells organizing into spheroids and undergoing 3D invasion of Matrigel demonstrated several typical angiogenic-like phenotypes dependent on basal levels of Angiopoeitin1-Tie2 signaling and ROCK activation. These results suggest that the ectopic sustained angiogenic environment during the early stages of valve disease promotes organized activity by both VECs and VICs, contributing to neovessel formation and the progression of CAVD.

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“…The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a coculture and transwell assays, it was shown that a secreted signal from endothelial cells inhibits calcification of porcine AVICs [16]. Nitric oxide (NO), which is secreted by endothelial cells, is critical for numerous physiologic and pathologic processes and had been implicated in the process of aortic valve calcification.…”

Section: Notch1 Signaling and Aortic Valve Calcificationmentioning

confidence: 99%

“…Conversely, increased nuclear localization of NICD was noted with the addition of NO donor. Lastly, the NOS3 and Notch1 signaling pathways genetically interact in vivo as NOS3;Notch1 compound mutant mice display a highly penetrant aortic valve disease [16]. These mice have highly penetrant BAV and develop hemodynamically significant aortic valve stenosis and regurgitation.…”

Section: Notch1 Signaling and Aortic Valve Calcificationmentioning

confidence: 99%

Notch Signaling in Aortic Valve Development and Disease

Garg

2016

Etiology and Morphogenesis of Congenital Heart Disease

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Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1 % in the population. BAV results in significant morbidity usually during adulthood due to its association with aortic valve calcification and ascending aortic aneurysms. Mutations in the signaling and transcriptional regulator, NOTCH1, are a cause of bicuspid aortic valve in non-syndromic autosomal dominant human pedigrees. The Notch signaling pathway is critical for multiple cellular processes during both development and disease and is expressed in the developing and adult aortic valve consistent with the cardiac phenotypes identified in affected family members. Recent work has begun to elucidate the molecular mechanisms underlying the link between Notch1 signaling and the development of BAV and valve calcification. Using in vitro approaches, loss of Notch signaling has been shown to contribute to aortic valve calcification via Runx2-, Sox9-, and Bmp2-dependent mechanisms. In addition, Notch1 signaling has been shown to be responsive to nitric oxide signaling during this disease process. A new highly penetrant mouse model of aortic valve disease using Notch1 haploinsufficient mice that are backcrossed in an endothelial nitric oxide synthase (Nos3)-null background was generated. Notch1 and Nos3 compound mutant mice (Notch1 þ/-;Nos3 -/-) display a nearly 100 % incidence of aortic valve malformations, most commonly BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. Based upon the initial discovery of NOTCH1 mutations in

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Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease

Cited by 152 publications

References 39 publications

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

Notch Signaling in Aortic Valve Development and Disease

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