A SIEVE-RAFT HYPOTHESIS FOR THE REGULATION OF ENDOTHELIAL FENESTRATIONS

Abstract

Fenestration morphology is a remarkable example of the synergy between structure and function. Through a better understanding of fenestration structure our understanding of its function will be enhanced. Fenestrations are transcellular pores that act as fundamental biological ultra-filters allowing diffusive and convective passage of substrates across cells without relying on endocytosis or other receptor-mediated mechanisms. They facilitate passive transfer of substances such as lipoproteins [1], parasites [2], pharmacological agents [3] and gene transfer vectors [4]. Fenestrated cells are highly conserved in evolution and have been documented in all species from fish to humans [5–9] and even in the phloem vascular system of higher plants [10]. In animals they are found in several cell types including liver sinusoidal endothelial cells (LSECs) [11] (Figure 1), glomerular endothelial cells [5], endothelial cells of the area postrema [12] and the posterior pituitary [13] of the brain, as well as numerous cancers [14]. All of these tissues require unimpeded transfer of substances between blood and surrounding cells. Fenestrations are essential for human health and loss of fenestrations in LSECs results in impaired lipid, drug and insulin transfer [15–17] and regeneration [18]. However, despite their ubiquity and biological importance, we are only beginning to understand the molecular and cellular pathways, and the spatial and temporal sequence of events involved in fenestration formation. Here, we propose a novel sieve-raft hypothesis [19] as a key mechanism regulating fenestrations in the LSEC. Figure 1 Microscopy of LSEC fenestrations and the LSEC membrane. Figure 1A is a scanning electron micrograph of an isolated LSEC in culture. The micrograph clearly displays fenestrations, examples are denoted by an asterix (*), arranged in groups (sieve plates) ...