Navarro-Aragall, Ariadna Gador;
(2019)
Mechanisms in murine cardiovascular development.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
The cardiovascular system is the first organ to develop in vertebrates. Cardiovascular development requires the coordination of several overlapping events that give rise to and then remodel the heart and its associated vascular structures into a network that effectively distributes blood into all organs without disrupting their tissue architecture. Neuropilin 1 (NRP1) is a transmembrane receptor that is required for the normal development of the cardiovascular system. NRP1 has binding sites for two crucial vascular regulators: vascular endothelial growth factor (VEGF) and class III semaphorins (SEMA3). During my PhD, I have examined the role of NRP1 and its ligands and co-receptors in the morphogenesis of the mammalian aortic arch. This highly asymmetric vessel complex originates in the embryo from 5 pairs of pharyngeal arch arteries (PAAs), which initially form in a rostro-caudal and symmetric fashion to connect the aortic sac with the dorsal aorta, but subsequently remodel to help separate the pulmonary and systemic circulation. Accordingly, failed PAA formation or remodelling causes congenital heart disease. I have examined Nrp1-null mice to define the time window in which NRP1 acts. Moreover, I have combined wholemount immunostaining with lineage tracing in mouse embryos to distinguish whether PAA formation involves NRP1 regulation of vasculogenesis from vascular progenitors, vessel sprouting/fusion from the dorsal aorta and aortic sac or neural crest/smooth muscle cell-mediated vascular remodelling. Finally, I have analysed tissue- and ligand-specific mutants to identify the cell types that rely on NRP1 signalling. My findings suggest that NRP1 has several consecutive roles at different stages of PAA morphogenesis. In a complementary study, I have contributed to work investigating molecular mechanisms that establish vascular exclusion zones in the embryonic mouse. I have found that two distinct SEMA3 proteins converge on the PLXND1 receptor to repel sprouting vessels around epithelia to limit vascular invasion of the developing motor column and bronchiolar smooth muscle and prevent excessive vessel sprouting around somites. My findings thereby add significantly to current knowledge of the regulatory interactions that underpin normal cardiovascular development and whose dysfunction causes congenial cardiovascular diseases.
Archive Staff Only
 |
View Item |
