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Cardiovasc Res. 2012 Mar 1;93(3):508-15. doi: 10.1093/cvr/cvr345. Epub 2011 Dec 22.

Gap junctional communication controls the overall endothelial calcium response to vasoactive agonists.

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Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 27, 81377 Munich, Germany.



A cytosolic calcium (Ca(2+)(i)) increase is an important activation signal for the endothelium. We investigated whether interendothelial spreading of the Ca(2+) signal via gap junctions (GJs) plays a role for the overall Ca(2+)(i) increase in response to vasoactive agonists.


In human umbilical vein endothelial cells (HUVECs), a Ca(2+)(i) increase (Fura2) in response to histamine or ATP occurred initially only in about 30% of the cells (initially responding cells) reflecting the cell fraction expressing H(1) or purinergic receptors (FACS/immunohistochemistry). In the remaining adjacent cells, Ca(2+)(i) increases occurred only after a delay of up to 5 s. Blockade of GJ communication (meclofenamic acid and heptanol, or H(2)O(2); verified by dye injection) did not affect responses in the initially responding cells but abolished the delayed Ca(2+)(i) response of the remaining adjacent cells. The resulting reduction in the global endothelial Ca(2+)(i) response significantly reduced the nitric oxide synthesis (assessed as cGMP levels). Similar Ca(2+)(i) results were obtained in the endothelium of freshly isolated mouse (C57BL/6) aortas stimulated with ATP. The receptor-independent Ca(2+)(i) response to ionomycin occurred simultaneously in all cells, regardless of GJ inhibition. In separate experiments, inhibition of the IP(3) receptor (xestospongin-C; 40, µmol/L) but not of the ryanodine receptor (ryanodine, 250 µmol/L) reduced the spread of the Ca(2+)(i) signal into adjacent cells over longer distances.


The global Ca(2+)(i) response of the endothelium to agonists is determined decisively by the functionality of GJs, thus establishing a new role for GJs in controlling endothelial activity and vasomotor function.

[Indexed for MEDLINE]

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