Endothelial Cyp26b1 restrains murine heart valve growth during development

• Published in: Developmental biology 2022-06, Vol.486, p.81-95
• Main Authors: Ahuja, Neha, Hiltabidle, Max S., Rajasekhar, Hariprem, Voss, Sophie, Lu, Steven Z., Barlow, Haley R., Cowdin, Mitzy A., Daniel, Edward, Vaddaraju, Vedha, Anandakumar, Thejal, Black, Ethan, Cleaver, Ondine, Maynard, Caitlin
• Format: Article
• Language: English
• Subjects: Animals; Aortic Valve; Cyp26b1; Endothelial cell proliferation; Endothelial Cells; Heart Valves - metabolism; Mice; Mitral valve; Morphogenesis; Organogenesis; Pulmonary valve; Retinoic Acid 4-Hydroxylase - genetics; Retinoic Acid 4-Hydroxylase - metabolism; Semilunar valve; Tretinoin - metabolism; Tricuspid valve
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2022.03.003

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. [Display omitted] •A mouse heart valve gene expression atlas was generated with publicly available online gene expression databases.•The endothelium of developing mouse heart valves is regionally heterogeneous.•Cyp26b1 is expressed in the endocardial/endothelial lining of developing heart valves.•Loss of Cyp26b1 leads to significant enlargement of aortic valves and to ventricular septal defects.•Retinoic acid targets are upregulated in Cyp26b1−/− heart valves, indicating dysregulation of RA metabolism.