Klotz, L; (2014) Characterization of the cardiac lymphatic vasculature. Doctoral thesis , UCL (University College London).

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Abstract

The lymphatic vasculature is a blind-ended network covering most tissues and organs of the body, crucial for tissue fluid homeostasis, immune surveillance and lipid adsorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. The major focus in the field has been on the systemic lymphatic vasculature, whilst organ-based lymphatics have been largely overlooked. In particular, the cardiac lymphatic vasculature has not been studied in great detail and the cellular origin of these vessels is yet to be determined. In contrast to the current dogma, the work presented in this thesis revealed that cardiac lymphatic vessels have a heterogeneous cellular origin. By utilizing multiple Cre transgenic mouse lines for lineage tracing studies and conditional Prox1 and Vegfr3 knockout mice, the data showed that the cardiac lymphatic vasculature is derived from both the blood and hemogenic endothelium during development. We hypothesized that the mechanisms underlying the development of the cardiac lymphatics might be reactivated following adult heart injury, therefore the innate cellular and molecular response of the cardiac lymphatic system to myocardial infarction (‘heart attack’) was investigated. A significant upregulation of lymphatic genes as well as a physical expansion of the lymphatic network via lymphangiogenesis was observed. These results prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and emphasize the significance of focusing on organ-based lymphatics during development and under pathological conditions. Specifically in the heart, this will enable better understanding of how to modulate the innate inflammatory response to promote cardiac wound healing and repair following myocardial infarction.

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