DOI: 10.25549/usctheses-c127-652666
title: Signaling pathways in cardiovascular development

description: Congenital cardiovascular disease is the number one birth defect causing deaths in the first year of life in children. The embryonic development of the heart involves various signaling pathways and multiple cell lineages, the interactions of which are critical for normal heart morphogenesis and function. Understanding these gene regulations and cell-cell interactions will provide insights for the molecular and cellular mechanisms underlying both cardiogenesis and cardiovascular disorders. In this thesis, we utilized the genetic modified mouse models to study the congenital cardiovascular diseases. ❧ Around one-third of congenital heart defects involve compromised outflow tract formation. Defects in the differentiation of the second heart field (SHF) result in shortened and misaligned outflow vessels, whereas defects in outflow tract septation result in a persisting single vessel. In this study, I found that as the initial SHF population differentiates and then incorporates into the outflow tract, it is replenished from a surrounding progenitor territory. This latter phase of SHF progenitor differentiation is dependent on retinoic acid (RA) signaling, which results in a shortened and misaligned outflow tract in mutant mice. In addition, as a consequence of this primary defect, the outflow tract of RA receptor mutant embryos becomes misspecified along its proximal-distal axis, as evidenced by ectopic expression of TGFβ2 and ectopic mesenchymal transformation of the endocardium. The reduction of TGFβ2 gene dosage in the RA receptor mutant background restores septation but does not rescue alignment defects, suggesting that ectopic TGFβ2 may cause excess or ectopic mesenchymal transformation of the endocardium that disrupts OFT organization and thereby results in septation failure. This work uncouples SHF differentiation from the later and indirect consequence on outflow tract septation. ❧ The outflow tract connects to systemic and pulmonary circulation through pharyngeal arch artery derived great vessels, the formation of which is a critical early step in the process that leads to the mature cardiovascular organization. We demonstrated here that the pharyngeal arch artery formation in mouse embryos is initiated by vasculogenesis, and in this process RA receptors in mesoderm cells autonomously control the coalescence of the angioblasts into nascent blood vessels. ❧ Ventricular chamber defects account for another large group of congenital heart diseases. Epicardium, the outmost layer of the heart, has been implicated as the source for mitogenic factors promoting the cardiomyocyte proliferation, although the specific factors involved have not been identified adequately. We found that during midgestation heart development, the embryonic epicardium expresses Igf2, the absence of which results in ventricular wall hypoplasia. Similarly, conditional disruption of the two IGF receptors genes Igf1r and Insr together in heart myocardium caused decreased myocardium proliferation. These results define IGF2 as a previously unexplored factor that is required for normal ventricular chamber development.