Loss of Gata5 in mice leads to bicuspid aortic valve

Laforest, Brigitte; Andelfinger, Grégor; Nemer, Mona

doi:10.1172/jci44555

Cited by 160 publications

(159 citation statements)

References 69 publications

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…Our results indicate that Notch1 is required within the endothelial cell lineage for proper OFT development and semilunar valve remodeling; however, the cell lineages with which Notch1 communicates have not been well defined. Similar to Notch1, deletion of Gata5 or Alk2 in the OFT endothelial (endocardial) and endothelial‐derived mesenchymal cells is sufficient to cause BAV 27, 28, 29. In addition, the cardiac neural crest is critical for the development of the cardiac OFT because loss of BMP signaling via the receptor ALK2 has been shown to cause persistent truncus arteriosus, improper cardiac neural crest migration causes OFT defects, and the loss of Rho kinase signaling within neural crest cells gives rise to BAV 30, 31, 32.…”

Section: Discussionmentioning

confidence: 99%

“…The process of leaflet fusion is currently not well understood because leaflet fusion may occur early in cushion development or later during valve remodeling. Gata5 knockout mice display BAV, which is caused by an early fusion without leaflet thickening, unlike that of ALK2 mutant mice, which demonstrate thickened valve leaflets at early stages 27, 30. Some studies have concluded that BAV subtypes are a result of specific genetic etiologies because Gata5 −/− mice and Nos3 −/− mice display BAVs with right–noncoronary fusion 27, 35.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Koenig

Bosse

Majumdar

et al. 2016

JAHA

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Koenig

Bosse

Majumdar

et al. 2016

JAHA

View full text Add to dashboard Cite

show abstract

“…Therefore, it is also rational to think about the management of associated complications of the ascending aorta. Untreated aortic aneurysm constitutes a life-threatening emergency and causes death by dilation and rupture [6,[24][25][26][27][28][29][30][31][32][33][34].…”

Section: Genes Associated With the Bavmentioning

confidence: 99%

Heart, Aorta and Aortic Valve Development and Cardiovascular Malformations

Mohamed¹

2017

Hum Genet Embryol

View full text Add to dashboard Cite

IntroductionIn vertebrates, the heart is the first organ to develop and takes shape during the third week of embryogenesis. The earliest evidence of a heart structure can be identified beginning from day 15 of pregnancy. Stem cells in the anterior-lateral mesoderm become specific cardiac precursor cells and align in a horseshoe shape. In the third week of pregnancy these heart precursor cells that are previously arranged in bilateral symmetrical manner move medially to unite and form a single primitive heart tube. This straight heart tube consists of an inner cell layer (endocardium), an outer cell layer (myocardium), and the extracellular matrix (ECM) separating the other two layers also known as the heart jelly.The developmental stage that follows is a right-hand rotation of the heart leading to the first left-right non-symmetry in the embryo. Because of this rotation, the segments of the heart tube that later form the atria are positioned above the segment that forms the ventricles. The atria, ventricles, and truncus arteriosus originate through local extensions of the heart tube during heart loop shaping. Simultaneously, the ECM within the outflow tract and the future atrioventricular channel expand to form so-called endocardial cushions. Heart-tube segmentation into atria, ventricles, and the outflow tract is accomplished by these cushions. By further growth and additional fusions, they form septum-and valve-structure precursors, separating the developing ventricles from each other.During the sixth and seventh week of pregnancy, the heart and the common outflow tract (truncus arteriosus) are chambered by the septa to divide into four distinct ventricles, the aorta, and the pulmonary artery. This results in the formation of a separate pulmonary and systemic circulation. The aorta and its respective segments originate from diverse embryonic structures. The ascending part of the aorta, the aorta ascenders is formed by the division of the truncus arteriosus as described above; however, the aortic arch and supra-aortic vessels originate from the third and fourth branchial arch arteries. The fivecomplete branchial arch artery pairs are also designated as aortic arches and originate from the truncus arteriosus, connecting it with the right and left dorsal aorta, which are also a part of the embryonic circulation. When the heart develops into the heart tube, valve morphogenesis also begins. The ECM in regions around the outflow tracts and between the atria and ventricles expand to form endocardial cushions, contributing to the formation of all four heart valves. During the next few days interactions between diverse endocardial and myocardial signals occur, which are of crucial importance for the transition remodeling of the endothelium and the mesenchyme. Following this transformation, mesenchymal cells proliferate and support further swelling of the endocardial cushions. In addition, myocardial cells infiltrate the edges of the endocardial cushions now containing mesenchymal cells [1][2][3][4][5].In the truncus ar...

show abstract

“…The development of a highly penetrant mouse model of BAV will assist in the dissection of the molecular pathways that lead to the development of this common cardiac malformation. Interestingly, mice deficient for Gata5 display partially penetrant BAV and have reduced expression of Nos3 and Notch signaling [17]. These mice also offer an opportunity to study the development of BAV-associated ascending aortic aneurysms.…”

Section: Future Directions and Clinical Implicationsmentioning

confidence: 99%

Notch Signaling in Aortic Valve Development and Disease

Garg

2016

Etiology and Morphogenesis of Congenital Heart Disease

View full text Add to dashboard Cite

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

show abstract

Loss of Gata5 in mice leads to bicuspid aortic valve

Cited by 160 publications

References 69 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

Heart, Aorta and Aortic Valve Development and Cardiovascular Malformations

Notch Signaling in Aortic Valve Development and Disease

Contact Info

Product

Resources

About