LOOKING THROUGH THE ’WINDOWS’ OF THE BRAIN VASCULATURE: MECHANISMS UNDERLYING THE PERMEABILITY OF FENESTRATED ENDOTHELIA IN THE ZEBRAFISH NEUROHYPOPHYSIS

The hypothalamo-neurohypophyseal system (HNS) is a major neuroendocrine interface through which the brain regulates body homeostasis by sensing the peripheral signals and releasing hypothalamic neuro-hormones to the blood circulation. This is facilitated by specialized fenestrated (i.e. permeable) blood capillaries, which have unique endothelial ultrastructural membranal pores (60-70 nm), dubbed fenestrae. But what regulates the bi-directional exchange of molecules between the brain and the general circulation? And what drives the HNS vessels to maintain vascular permeability instead of forming BBB?

To answer these questions, we developed novel transgenic tools to visualize vascular permeability in vivo and performed ultrastructural analyses of the HNS vasculature in zebrafish. By employing quantitative fluorescent photobleaching recovery (FRAP) analysis in live zebrafish embryos we provide a direct proof that the fenestrae associated protein PLVAP regulates the transfer of plasma proteins from blood into the HNS parenchyma [1]. We have found that the resident pituitary glial cells, namely pituicytes, provide local microenvironmental cues that drive the HNS vasculature to adopt permeable fate rather than forming BBB[2]. Altogether, we present novel regulatory mechanisms underlying the development and function of the fenestrated capillaries in the major brain-to-body conduit, the HNS.

1. Ludmila Gordon, Janna Blechman, Eyal Shimoni, Dvir Gur, Bela Anand-Apte, Gil Levkowitz. Fenestrae-associated protein Plvap regulates the rate of blood-borne proteins passage into the hypophysis. BioRxiv 571299 [Preprint]. March 2019. Available from: https://doi.org/10.1101/571299

2. Anbalagan, Savani, Ludmila Gordon, Janna Blechman, Ryota L. Matsuoka, Preethi Rajamannar, Einav Wircer, Jakob Biran, et al. "Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces." Developmental Cell 47, no. 6 (2018): 711-26.e5.