Deficient Signaling via Alk2 (Acvr1) Leads to Bicuspid Aortic Valve Development

Abstract

Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly in humans. Despite recent advances, the molecular basis of BAV development is poorly understood. Previously it has been shown that mutations in the Notch1 gene lead to BAV and valve calcification both in human and mice, and mice deficient in Gata5 or its downstream target Nos3 have been shown to display BAVs. Here we show that tissue-specific deletion of the gene encoding Activin Receptor Type I (Alk2 or Acvr1) in the cushion mesenchyme results in formation of aortic valve defects including BAV. These defects are largely due to a failure of normal development of the embryonic aortic valve leaflet precursor cushions in the outflow tract resulting in either a fused right- and non-coronary leaflet, or the presence of only a very small, rudimentary non-coronary leaflet. The surviving adult mutant mice display aortic stenosis with high frequency and occasional aortic valve insufficiency. The thickened aortic valve leaflets in such animals do not show changes in Bmp signaling activity, while Map kinase pathways are activated. Although dysfunction correlated with some pro-osteogenic differences in gene expression, neither calcification nor inflammation were detected in aortic valves of Alk2 mutants with stenosis. We conclude that signaling via Alk2 is required for appropriate aortic valve development in utero, and that defects in this process lead to indirect secondary complications later in life.

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

“…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.…”

Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve

“…Similarly, ACTA2 has been shown via linkage analysis to be associated with BAV occurring with aortic aneurysm (21). Murine models have suggested roles for Alk2, Nkx2.5 and Nos3 in BAV formation, but there have been no reported mutations of these genes in cases of human BAV (22–25). Additional investigation is required in the BAV population as there may be roles for GATA4 and GATA6, mutations in which have been associated with other types of human CHD (26–28).…”

Genetics of Valvular Heart Disease

“…This model demonstrates the ability of uncleaved versican and insufficient Smad2 phosphorylation to cause bicuspid aortic and pulmonic valves [42]. Another member of the Bmp signaling pathway has also been implicated in BAV in mice as recent studies have also shown that the tissue specific deletion of Activin Receptor Type I ( Alk2 ), in the endocardial cushion mesenchyme at post-EMT stages, resulted in BAV [43]. Additional investigations of nitric oxide and Bmp signaling pathways are required to determine if these findings will translate to the genetics of human BAV.…”