| Summary: | The cardiovascular system is the first functional organ system to develop in vertebrates. It links all other organ systems and is essential for normal development. The blood-brain barrier (BBB) is a highly selective semi-permeable interface between blood vessels and the brain. How the selective permeability of the BBB is established during development remains poorly understood. Here, I have identified that in zebrafish, Adrenomedullin signalling via Calcrl/Ramp2 promotes the normal development of the blood vascular network. Genetic variants in CALCRL and RAMP2 and their regulatory elements are associated with predisposition to human diseases including stroke and coronary artery disease. In mice, embryonic lethality prevents detailed characterisation of the function of Adrenomedullin signalling during development. Furthermore, the roles of Adrenomedullin signalling have been disputed, with some studies reporting defective lymphatic specification and others reporting reduced vascular integrity. Therefore, understanding the mechanisms by which Adrenomedullin signalling regulates zebrafish cardiovascular development may help to improve understanding of the role of Adrenomedullin signalling during cardiovascular development. Ultimately, this may aid development of effective therapeutics targeting human cardiovascular diseases.
Zebrafish Adrenomedullin signalling-deficient mutants display widespread oedema similar to the hydrops fetalis phenotype observed in Adrenomedullin signalling-deficient mouse mutants. Adrenomedullin signalling co-ordinates multiple aspects of brain barrier formation and function in zebrafish. Zebrafish Adrenomedullin signalling-deficient mutants display defects in the establishment of the BBB in the cranial vasculature. The role of Adrenomedullin during neurovascular development is dose-dependent. Low levels of Adrenomedullin signalling are required to promote vascular integrity within the cranial vasculature and higher levels of Adrenomedullin signalling are required to suppress transcytosis across the BBB. While primary angiogenesis is independent of Adrenomedullin signalling, Adrenomedullin signalling mediates formation of the choroid vascular bed by promoting formation of the dorsal longitudinal vein in a Vegfc-dependent manner. Adrenomedullin signalling is also required for stereotypical cardiac function and to limit constrictive remodelling of trunk blood vessels highlighting the complex roles of Adrenomedullin signalling during the formation of the cardiovascular system. Interestingly, Adrenomedullin signalling is dispensable for lymphatic specification and lymphangiogenesis, revealing a divergence in lymphatic specification mechanisms between fish and mammals.
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