Signaltransduction in vascular endothelium: the role of intracellular calcium and ion channels.

Endothelial cells (ECs) provide an ideal surface for blood flow. They inhibit the initiation of blood-clotting, but can also under certain conditions activate this process. ECs influence thrombolysis as well as thrombogenesis. They are "antigen-presenting cells" and play a key role in angiogenesis. In addition, ECs control the permeability of the barrier between bloodvessels and interstitium. One of their most important functions is the regulation of the diameter of the blood vessels and their adaptation to the demanded hemodynamic needs. The production and release of diverse compounds, which interfere with different neighboured target cells, initiate this plethora of functions. Ca2+ signals in endothelial cells play the key role in the release of NO, prostacyclin (PGI2), platelet activating factor (PAF), von Willebrand factor (vWF), tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI). Changes in the intracellular Ca2+ concentration ([Ca2+]i) are determined by release from intracellular stores and entry through the plasma membrane. The diversity of Ca2+ entry pathways and mechanisms of their control are described. At least two different types of Ca2+ entry channels exist: 1. typical highly Ca2+ selective ion channels which might be activated by depletion of intracellular Ca2+ stores (Ca2+ release-activated Ca2+ channels, CRAC), and 2. Non-selective Ca2+ permeable cation channels (NSC). The latter shares many features with an NSC induced by expression of the protein TRPC3. These channels are only weakly operated by store depletion and require a permissive Ca2+ and Ins(1,4,5)P3 concentration in the cytosol. CRAC channels are possible indirectly involved in Ca2+ entry during mechano-stimulation of ECs. After activation of these entry channels, influx of Ca2+ depends on the driving force. The following ion channels play a pivotal role in regulation of the driving force for Ca2+ entry: an inwardly rectifying K+ channel, identified as Kir2.1, a large-conductance, Ca2+ activated K+ channel (hslo) and at least two Cl- channels (a volume regulated Cl- channel, VRAC, and a Ca2+ activated Cl- channel, CaCC). It will be explained how these ion channels interact in the regulation of the long-lasting (plateau-type) increase in [Ca2+]i which mainly controls NO-synthesis and release. Furthermore, it will be demonstrated that Ca2+ oscillations depend on intracellular events rather than Ca2+ entry from the extracellular space.