Dr Weber is tackling the question of the control of leukocyte arrest and emigration into the vessel wall in the context of atherogenesis. His talk emphasised the importance of blood platelets in modulating leukocyte adhesion, demonstrating that their local adherence leads to the secretion of chemokines that then bind to endothelium and consequently attract leukocytes – thus bringing back into fashion the concept that platelet reactivity contributes to the earliest phase of atherogenesis as well as to the final events. He is currently designing peptides that selectively disrupt these chemokine-receptor interactions as lead compounds for new therapeutic approaches to impair atherogenesis.
Dr Hirschi is analysing the mechanisms by which endothelial cells recruit extramural cells in new vessels and direct their differentiation into pericytes. She provided elegant data using in vitro cell co-culture models that show clearly that gap junction communication between endothelial cells and mural cells is required for their differentiation. Intriguingly, however, it seems that phosphorylation of the cytoplasmic tail of the gap junction protein connexin 43 or 45 when cell contact is made, rather than ionic communication per se, is critical for causing differentiation. The mechanism is not yet fully understood, but involves control of TGFβ activation, already known to be necessary.
Dr Tyml is examining electrical coupling via connexins between adjacent endothelial cells and their role in coducted vasomotor responses. He showed in vitro data indicating that hypoxia followed by rapid reoxygenation led to a transient deficit in coupling that was attributable to loss of protein kinase A activity that maintains patent connexin 40 gap junctions. In vivo, he found impaired conducted vasoconstriction by similar mechanisms when vessels were subjected to ischemia followed by reperfusion.
Dr Kuebler studies the pulmonary alveolar compartment and has demonstrated that NO generation by the pulmonary capillary endothelium is increased by increased hydrostatic pressure. He showed that the NO not only contributes to tightening the capillary permeability barrier, but by diffusion to the alveolar epithelium additionally acts to reduce alveolar fluid reabsorption across the epithelial permeability barrier. This may therefore represent a novel mechanism that leads to cardiogenic pulmonary edema when pressure is increased pathologically.
Conclusion
These 4 talks described recent advances in understanding communication between cells of the vessel wall and neighbouring cells; moving from the description of communication by cell to cell contact to communication via electrical coupling and finally gaseous coupling.
Collectively they emphasise that cells of the vessel wall must continually maintain accurate and modulatable communication with neighbouring cells to ensure correctly integrated physiological responses to alterations in the external environment.
Notes to editor
Presenters: Prof Christian Weber (Germany) “Cross-talk between blood cells in inflammation”, Prof Karen Hirchi (USA) “Control of angiogenesis by the pericyte”, Prof K Tyml (Canada) “Hypoxia reoxygenation and endothelial cell coupling” and Prof Wolfgang Kuebler (Germany) “Intercompartmental communication in the lung microvasculature”
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European Society of Cardiology.