Transient increase in VEGF‐A leads to cardiac tube anomalies and increased risk of congenital heart malformations

Abstract

Vascular endothelial growth factor (VEGF) plays a critical role during early heart development. Clinical evidence shows that conditions associated with changes in VEGF signaling in utero are correlated with an increased risk of congenital heart defects (CHD) in newborns. However, how malformations develop after abnormal VEGF exposure is unknown. During embryogenesis, a primitive heart, consisting of an endocardial tube enveloped by a myocardial mantle, is the first organ to function. This tubular heart ultimately transforms into a four-chambered heart. To determine how a transient increase in VEGF prior to heart tube formation affects heart development leading to CHD, we applied exogenous VEGF or a control (vehicle) solution to quail embryos in ovo at Hamburger-Hamilton (HH) stage 8 (28-30 hr of incubation), right before heart tube formation. Light microscopy analysis of embryos reincubated after treatment for 13 hrs (to approximately HH11/HH12) showed that increased VEGF leads to impaired heart tube elongation accompanied by diameter expansion. Micro-CT analysis of embryos re-incubated for 9 days (to approximately HH38), when the heart is fully formed, showed that VEGF treatment increased the rate of cardiac malformations in surviving embryos.Despite no sex differences in survival, female embryos were more likely to develop cardiac malformations. Our results further suggest that heart tube malformations after a transient increase in VEGF right before heart tube formation may be reversible, leading to normal hearts.

Imbalance of fetal growth factor levels in congenital heart disease pathology: a systematic review to investigate therapeutic potential

“…This growth requires the growth of the fetus, which requires a balance of the amount of secretion of this substance and the timing of its reception by the fetus (39). Before the formation of the heart, a suitable dose of VEGF will cause the formation of cardiovascular tubes and the beginning of fetal tissue differentiation (40), but as Rykiel showed, shortly before the complete formation of the heart, the increase in VEGF has no effect other than disruption of the heart cavities and tubes (19). An increase in VEGF and other angiogenic factors during CHD and an imbalance in the development of the heart and blood vessels are considered the main causes of heart defects.…”

Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review

“…The vascular endothelial growth factor (VEGF) family is essential for angiogenesis, and the pathway involving these signaling molecules is also a key regulator of heart morphogenesis [104]. VEGFA plays an important role in the early stages of heart development, influencing the formation of the heart tube, and its overexpression can lead to impaired heart tube elongation and looping [105]. In addition, it is involved in the development of the endocardial cushions by mediating the endothelial-to-mesenchymal transition; thus, alterations in the expression of VEGFA may lead to atrioventricular septal defects and dysplastic atrioventricular valves [106].…”