Sarah Schnabellehner: Exploring Vascular Specialization at the Organotypic and Cellular Levels

Abstract

The lymphatic system is a unidirectional network that drains fluid and macromolecules, consisting of functionally specialized lymphatic capillaries and collecting vessels. Similarly, the blood vascular system is composed of the functionally arteries, capillaries, and veins, which together enable the distribution of oxygen and nutrients. Certain tissues exhibit organ-specific vascular adaptations, including hybrid vascular identities that combine features of different vessel types. In Paper I, I identified the penile cavernous sinusoids (pc-Ss) as a novel hybrid vascular bed that maintains both blood and lymphatic vessel-specific characteristics in both mice and humans. Notably, this highly specialized PROX1-positive vascular bed developed independently of the key lymphangiogenic growth factor VEGF-C, distinguishing it from other lymphatic and hybrid vessels analyzed so far.

The vascular system is continuously subjected to mechanical forces generated by fluid flow, including laminar and turbulent flows in different vessel segments. Unique to the lymphatic system, the oak leaf-shaped lymphatic endothelial cells (LECs) that line the capillaries and facilitate the uptake of interstitial fluid are primarily subjected to transmural flow and isotropic stretch, caused by fluid uptake-induced changes in vessel caliber. To investigate how capillary LECs adapt to these mechanical stressors at the cellular level, I established in Paper IIin vitro models that mimic transmural flow and isotropic stretch. Using these models, in Paper III, I identified cyclic isotropic stretch as a driver of key features associated with capillary LECs in vivo, including prominent cellular overlaps and curvature of cell-cell contacts. We also found that dynamic remodeling of capillary LEC overlaps and the cytoskeleton is essential to maintaining monolayer integrity during isotropic stretch in vitro and in homeostasis in vivo. This process is mediated through a CDC42-dependent mechanism independent of integrin ß1.

In summary, this thesis provides new molecular and functional insights into organ-specific vascular heterogeneity, which may ultimately help identify targets for the development of improved therapies for conditions such as dysregulated penile vasculature or lymphedema. Furthermore, by applying new tools to study different mechanical forces in vitro, this thesis uncovers how publisherpus contribute to the functional specialization of LECs and regulate the homeostatic maintenance of lymphatic vessels - insights that may be applicable to other vascular beds.