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Updated: May 12, 2026
Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta
Published on: September 12, 2017
Identification of novel buffering mechanisms in aortic arch artery development and congenital heart disease
Insights
Embryonic heart development is robust due to compensatory endothelial cells. This study reveals how VEGFR2 and Tbx1 regulate these cells, preventing congenital heart disease.
Area of Science:
- Developmental Biology
- Cardiovascular Research
- Genetics
Background:
- Embryonic development exhibits remarkable resilience to perturbations, yet the mechanisms ensuring robustness remain unclear.
- Congenital heart disease (CHD) often results from defective pharyngeal arch artery (PAA) development, highlighting critical gaps in understanding developmental processes.
Approach:
- Investigated the role of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and T-box transcription factor 1 (Tbx1) in PAA morphogenesis.
- Examined the contribution of second heart field (SHF)-derived endothelial cells (ECs) and compensatory ECs from adjacent veins.
- Utilized genetic manipulation (VEGFR2 and Tbx1 deletion models) and analyzed EC connectivity, fate, and gene expression.
Key Points:
- VEGFR2 expression in the SHF is crucial for PAA endothelium differentiation; VEGFR2 deficiency leads to reduced SHF contribution.
- Compensatory ECs from nearby veins rescue PAA development in VEGFR2 mutants, but blocking this compensation causes embryonic lethality.
- Tbx1 is essential for recruiting these compensatory ECs, and its absence in Tbx1 mutants leads to unpredictable PAA morphogenesis and CHD.
Conclusions:
- Uncovered a novel buffering mechanism involving compensatory endothelium that ensures PAA development resiliency.
- Identified VEGFR2 and Tbx1 as key regulators of EC recruitment and PAA morphogenesis, offering insights into CHD etiology.
- Demonstrated the critical role of SHF-non-cell-autonomous Tbx1 function in preventing PAA defects and embryonic lethality.
Rationale:
The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease (CHD) arising from defective morphogenesis of pharyngeal arch arteries (PAA) and their derivatives.
Objective:
To uncover mechanisms underlying the robustness of PAA morphogenesis.
Methods And Results:
The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived ECs is regulated by VEGFR2 and Tbx1 . Remarkably, when SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated three-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of one VEGFR2 allele (VEGFR2 SHF-HET ) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (VEGFR2 SHF-KO ) abolishes it. The decrease in SHF-derived ECs in VEGFR2 SHF-HET and VEGFR2 SHF-KO embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in VEGFR2 SHF-KO mutants. Blocking the compensatory response in VEGFR2 SHF-KO mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in Tbx1 embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and CHD. Tbx1 regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner.
Conclusions:
Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.
Nonstandard Abbreviations And Acronyms In Alphabetical Order:
CHD - congenital heart disease; ECs - endothelial cells; IAA-B - interrupted aortic arch type B; PAA - pharyngeal arch arteries; RERSA - retro-esophageal right subclavian artery; SHF - second heart field; VEGFR2 - Vascular endothelial growth factor receptor 2.
