@article{12e0765d4ab04d38801e61a81d9ba2f9,
title = "Endothelial Cyp26b1 restrains murine heart valve growth during development",
abstract = "Endothelial cells (ECs) are critical to proper heart valve development, directly contributing to the mesenchyme of the cardiac cushions, which progressively transform into mature valves. To date, investigators have lacked sufficient markers of valve ECs to evaluate their contributions during valve morphogenesis fully. As a result, it has been unclear whether the well-characterized regional differentiation of valves correlates with any endothelial domains in the heart. Furthermore, it has been difficult to ascertain whether endothelial heterogeneity in the heart influences underlying mesenchymal zones in an angiocrine manner. To identify regionally expressed EC genes in the heart valves, we screened publicly available databases and assembled a toolkit of endothelial-enriched genes. We identified Cyp26b1 as one of many endothelial enriched genes found to be expressed in the endocardium of the developing cushions and valves. Here, we show that Cyp26b1 is required for normal heart valve development. Genetic ablation of Cyp26b1 in mouse embryos leads to abnormally thickened aortic valve leaflets, which is due in part to increased endothelial and mesenchymal cell proliferation in the remodeling valves. In addition, Cyp26b1 mutant hearts display ventricular septal defects (VSDs) in a portion of null embryos. We show that loss of Cyp26b1 results in upregulation of retinoic acid (RA) target genes, supporting the observation that Cyp26b1 has RA-dependent roles. Together, this work identifies a novel role for Cyp26b1 in heart valve morphogenesis and points to a role of RA in this process. Understanding the spatiotemporal expression dynamics of cardiac EC genes will pave the way for investigation of both normal and dysfunctional heart valve development.",
keywords = "Aortic valve, Cyp26b1, Endothelial cell proliferation, Mitral valve, Pulmonary valve, Semilunar valve, Tricuspid valve",
author = "Neha Ahuja and Hiltabidle, {Max S.} and Hariprem Rajasekhar and Sophie Voss and Lu, {Steven Z.} and Barlow, {Haley R.} and Cowdin, {Mitzy A.} and Edward Daniel and Vedha Vaddaraju and Thejal Anandakumar and Ethan Black and Ondine Cleaver and Caitlin Maynard",
note = "Funding Information: This work was supported by the National Heart Lung and Blood institute ( HL113498 to O.C.); the National Institute of Diabetes and Digestive and Kidney Diseases ( DK106743 , DK079862 to O.C.); and a Graduate Research Fellowship ( 2019241092 to H.R.B.). Deposited in PMC for release after 12 months. Funding Information: Initially, we thought that there might be a role for RA-mediated induction of apoptosis in OFT cushions. Others have shown that apoptosis is increased in OFT cushions of RXRa?/? mutant mouse hearts (Kubalak et al., 2002), indicating a requirement for RA mediation of cell death in the developing OFT. Work from the Epstein lab has shown that cNCCs are required to stimulate mesenchymal cell apoptosis during late-stage remodeling and valvular thinning in the OFT (Jain et al., 2011). Intriguingly, their mouse models of cNCC-deficient OFTs displayed dysmorphic and thickened SL valves, similar to the Cyp26b1?/? aortic valve leaflets. Since cell death is required for proper valve leaflet elongation and remodeling, and RA signaling induces apoptosis in the OFT, it is possible that loss of Cyp26b1 interferes with cNCC-mediated mesenchymal cell apoptosis and remodeling. However, our data (Fig. S6E) shows that cell death is not changed in Cyp26b1?/? hearts. Furthermore, pulmonary valve elongation and remodeling were relatively unaffected by loss of Cyp26b1 in our mouse model, supporting the idea that the aortic valve defects and VSD may be cNCC-independent.This work was supported by the National Heart Lung and Blood institute (HL113498 to O.C.); the National Institute of Diabetes and Digestive and Kidney Diseases (DK106743, DK079862 to O.C.); and a Graduate Research Fellowship (2019241092 to H.R.B.). Deposited in PMC for release after 12 months. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jun,
doi = "10.1016/j.ydbio.2022.03.003",
language = "English (US)",
volume = "486",
pages = "81--95",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
}