Dynamics Of The Lymphatic Microvasculature: Relationships Between Lymphangiogenesis And Angiogenesis
The blood and lymphatic vascular systems coordinate to play critical roles in tissue fluid homeostasis and immune function and are fundamentally associated with diseases including inflammation, wound healing, edema, and tumor progression and metastasis. Their coordination during vascular growth and remodeling represents an under-investigated area of research in which a better understanding will provide insights into future therapeutic approaches. Angiogenesis and lymphangiogenesis are the growth of new blood or lymphatic vessels, respectively, from pre-existing vessels. The comprehensive goal of this work was to provide a new perspective on the relationships between angiogenesis and lymphangiogenesis in microvascular networks and develop tools needed to probe the mechanisms involved in lymphatic/blood vessel patterning and identity. The first aim of this study was to characterize the spatiotemporal relationships between lymphatic and blood vessel growth in response to an inflammatory stimulus. We found that lymphangiogenesis temporally lagged angiogenesis during inflammation and that the presence of lymphatic vessels attenuated angiogenesis. We also identified increased lymphatic/blood endothelial cells connections and a novel lymphatic marker. These results motivated the need for a system to probe the multicellular and multisystem interactions suggested by these findings. Our lab recently developed the rat mesentery culture model as an ex vivo model for investigating angiogenesis in the context of intact microvascular networks. The second aim was to determine whether this model can be used to study lymphangiogenesis. We found that vascular endothelial growth factor C stimulated lymphatic sprout formation in the rat mesentery culture model and confirmed the ability to observe angiogenesis and lymphangiogenesis simultaneously in an ex vivo environment. This suggests the rat mesentery culture model can be used to investigate the dynamics of lymphatic/blood vessel patterning and plasticity motivated by our in vivo work. The final aim of this work was to investigate the ability to induce phenotypic plasticity in intact vasculature by using lysophosphatidic acid, an agonist suggested to cause blood-to-lymphatic endothelial cell transition. We demonstrated that while lysophosphatidic acid stimulated angiogenesis, it was not sufficient to reprogram blood vessels to acquire a lymphatic phenotype. These results underscore the necessity of investigating these multisystem relationships in the context of intact microvascular networks. These studies as a whole demonstrate the coordination that exists between blood and lymphatic vessels and reinforce the need for novel models that incorporate the complexities of the entire microvasculature.