Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells.
BACKGROUND
In endothelial cells, caveolin-1, the structural protein of caveolae, acts as a scaffolding protein to cluster lipids and signaling molecules within caveolae and, in some instances, regulates the activity of proteins targeted to caveolae. Specifically, different putative mediators of the endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation are located in caveolae and/or regulated by the structural protein caveolin-1, such as potassium channels, calcium regulatory proteins, and connexin 43, a molecular component of gap junctions.


RESULTS
Comparing relaxation in vessels from caveolin-1 knockout mice and their wild-type littermates, we observed a complete absence of EDHF-mediated vasodilation in isolated mesenteric arteries from caveolin-1 knockout mice. The absence of caveolin-1 is associated with an impairment of calcium homeostasis in endothelial cells, notably, a decreased activity of Ca2+-permeable TRPV4 cation channels that participate in nitric oxide- and EDHF-mediated relaxation. Moreover, morphological characterization of caveolin-1 knockout and wild-type arteries showed fewer gap junctions in vessels from knockout animals associated with a lower expression of connexins 37, 40, and 43 and altered myoendothelial communication. Finally, we showed that TRPV4 channels and connexins colocalize with caveolin-1 in the caveolar compartment of the plasma membrane.


CONCLUSIONS
We demonstrated that expression of caveolin-1 is required for EDHF-related relaxation by modulating membrane location and activity of TRPV4 channels and connexins, which are both implicated at different steps in the EDHF-signaling pathway.
Saliez
J
J
Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Medical School, Brussels, Belgium.
Bouzin
C
C
Rath
G
G
Ghisdal
P
P
Desjardins
F
F
Rezzani
R
R
Rodella
L F
LF
Vriens
J
J
Nilius
B
B
Feron
O
O
Balligand
J-L
JL
Dessy
C
C
D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology*; D017630:Connexins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D017629:Gap Junctions / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
D001685:Biological Factors; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D017630:Connexins; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D002118:Calcium