Identification of compensatory mechanisms to rescue aortic arch artery defects

PROJECT SUMMARY The aortic arch artery and its branches are blood vessels that route the oxygenated blood
from the heart to the systemic circulation. Defects in the development of the aortic arch artery lead to lethal forms
of congenital heart disease (CHD) due to interruption(s) in the systemic circulation, for example, the interrupted
aortic arch type B (IAA-B). These defects often occur in conjunction with 22q11 deletion syndrome, the most
common congenital chromosomal abnormality syndrome in humans. Therefore, understanding genes and
mechanisms regulating the development of the aortic arch artery will provide valuable insights into CHD etiology
and potential treatments. Aortic arch artery and its branches form following the remodeling of the symmetrical
pharyngeal arch arteries (PAAs) into the asymmetrical vascular tree. We demonstrated that the PAA endothelium
is mainly derived from progenitors in the second heart field (SHF). Furthermore, we found that genetic mutations
resulting in the deficiency in the SHF-derived endothelium cause IAA-B. This grant application describes two
new mouse models in which an unexpected source of endothelial progenitors repairs the deficiency in the SHF-
derived endothelial cells (ECs) and rescues aortic arch artery formation. Our discovery of an alternative
endothelial source that repairs PAA defects has opened the possibility to determine mechanisms regulating this
compensatory repair process. We also discovered that the compensatory endothelium is not recruited in the
Tbx1+/- mouse model of 22q11 deletion syndrome, resulting in IAA-B and neonatal lethality in ~65% of Tbx1+/-
mice. In this grant application, we propose to determine the source of compensating ECs, mechanisms regulating
the recruitment of compensatory endothelium, and how Tbx1 regulates this process. To accomplish these goals,
we propose the following Specific Aims: 1 To test the hypothesis that the compensating endothelium is derived
from a vein, and 2 To determine signals regulating the recruitment of the compensatory ECs to rescue arch
artery formation. In this proposal, we will use novel mouse strains, genetic engineering, quantitative 3D confocal
imaging, in situ hybridization, and RNAseq to uncover candidate genes regulating the compensatory response.
Upon completing the proposed work, we will uncover innate mechanisms of compensation and robustness,
whereby a newborn's viability is ensured through alternative mechanisms. Harnessing these mechanisms would
provide new opportunities for treatments of CHD in the future.

Grant Number: 5R01HL158049-04
NIH Institute/Center: NIH
Principal Investigator: Sophie Astrof