In his treatise ‘Longevity and the causes of natural death’De-Martel (1688) wrote: ‘We must therefore enquire into other more true causes of old age and death, which to me seem to be the following. I suppose, that blood is the principle of life, as far as it is vital, that is, in motion by the hot particles contained therein; those who expire by age, do not die for being destitute of blood, but because it ceases to be vital, by reason of too early dissipation of the igneous particles, which in my opinion come to pass, as it doth in wine, which evaporates and loses its strength by the fault of the vessel, which by some opening or other gives passage to what gives virtue to wine. The tunicles and membranes of the veins and arteries which enclose blood, wear in time and wax thin, and their texture gives and breaks in several places, at which apertures the igneous particles abandon the blood. If we have the art to reinforce and strengthen anew the coats and membranes, that they might not let slip what maketh the blood vital, then life would be preserved perpetually.’ More than three centuries later, despite the discovery of key adhesion molecules which bind endothelial cells together, surface receptors which phosphorylate upon occupation and intracellular signalling molecules, we are still far from understanding the signalling pathways which modulate endothelial permeability. In fact the very transport pathways used, paracellular or transcellular, are still a matter of debate. During inflammatory events, does increased permeability result from opening of paracellular junctions or the formation of vesicular channels from luminal to abluminal surfaces? Moreover, within the paracellular pathway, the role of tight junctions and adherens junctions in determining barrier properties varies according to location of the vascular bed. In the blood–brain barrier, it is clear that the tight junctions, with a complex network of continuous junctional strands, control permeability. The role of tight junctions becomes accessory in systemic vessels where adherens junctions predominate in the paracellular clefts. Transgenic animal and in vitro studies have shown that molecules present in adherens junctions have a significant impact on both vascular permeability and angiogenesis. The discovery of a family of water channel proteins, the aquaporins, which are expressed in many endothelial and epithelia, has spawned research into another important mechanism by which fluid is transported across these cells. The molecules present in cell–cell and cell–matrix junctions clearly have functions beyond adhesion, being important signal transduction ligands vulnerable to both ‘inside-out’ and ‘outside-in’ signalling. In addition to inflammatory mediators such as histamine, hydrogen peroxide, thrombin and bradykinin, the so-called angiogenic growth factors VEGF and angiopoietins have clearly demonstrable roles in influencing vascular permeability and determining junctional integrity. VEGF is also an important survival factor. Where and whether the signalling pathways determining angiogenesis, endothelial survival and permeability meet may be the quest of the early years of the 21st century. Only then will it be possible to develop therapeutic interventions that can restore vascular integrity – a goal held so dear by de Martel. The clinical benefits of such interventions will be enormous, since many conditions (e.g. diabetic microangiopathy, sepsis, ischaemia and neoplasia to name but a few) all feature impaired endothelial permeability in their symptomatology. The symposium brought together anatomists, molecular biologists and physiologists to develop an integrated view of endothelial cell permeability. The reviews presented in this volume describe some of the recent exciting advances in the field of endothelial cell biology and provide a synthesis of molecular and structural approaches to understanding endothelial permeability. We believe that the contents of this volume will be widely cited and we were privileged to be able to organize the symposium and edit this thought-provoking issue of the Journal of Anatomy.
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