Limits...
Ovariectomy-induced reductions in endothelial SK3 channel activity and endothelium-dependent vasorelaxation in murine mesenteric arteries.

Yap FC, Taylor MS, Lin MT - PLoS ONE (2014)

Bottom Line: The results from functional studies using isolated murine mesenteric arteries show that ovx reduces ACh-induced endothelium-dependent vasodilation due to decreased EDH and NO contributions, although the contribution of PGI2 is upregulated.The decreased EDH-mediated vasorelaxation in ovx vessels is due to reduced SK3 channel contribution to the pathway.Further, whole-cell recordings using dispersed endothelial cells also show reduced SK3 current density in ovx endothelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of South Alabama, Mobile, Alabama, United States of America.

ABSTRACT
Mesenteric artery endothelium expresses both small (SK3)- and intermediate (IK1)-conductance Ca(2+)-activated K(+) (KCa) channels whose activity modulates vascular tone via endothelium-dependent hyperpolarization (EDH). Two other major endothelium-dependent vasodilation pathways utilize nitric oxide (NO) and prostacyclin (PGI2). To examine how ovariectomy (ovx) affects the basal activity and acetylcholine (ACh)-induced activity of each of these three pathways to vasorelaxation, we used wire myograph and electrophysiological recordings. The results from functional studies using isolated murine mesenteric arteries show that ovx reduces ACh-induced endothelium-dependent vasodilation due to decreased EDH and NO contributions, although the contribution of PGI2 is upregulated. Both endothelial SK3 and IK1 channels are functionally coupled to TRPV4 (transient receptor potential, vanilloid type 4) channels: the activation of TRPV4 channels activates SK3 and IK1 channels, leading to EDH-mediated vascular relaxation. The decreased EDH-mediated vasorelaxation in ovx vessels is due to reduced SK3 channel contribution to the pathway. Further, whole-cell recordings using dispersed endothelial cells also show reduced SK3 current density in ovx endothelial cells. Consequently, activation of TRPV4 channels induces smaller changes in whole-cell current density. Thus, ovariectomy leads to a reduction in endothelial SK3 channel activity thereby reducing the SK3 contribution to EDH vasorelaxation.

Show MeSH

Related in: MedlinePlus

IK1 channel activity mediates TRPV4-induced vasorelaxation in ovx vessels.A: Summarized results from studies using 500 nM HC067047 (HC), a TRPV4 channel antagonist, on change in tone (left panel) and contribution to ACh-induced relaxation (right panel) using vessels obtained from both control (black) and ovx (grey) mice. B: Summarized results from studies using 300 nM GSK1016790, a TRPV4 channel agonist, on changes to vascular tension in the absence and presence of apamin (apa) and/or tram34 (tram). These studies were performed in the presence of L-NAME and indomethacin. Asterisk (*) denotes statistical significance (P<0.05, t-test).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126749&req=5

pone-0104686-g004: IK1 channel activity mediates TRPV4-induced vasorelaxation in ovx vessels.A: Summarized results from studies using 500 nM HC067047 (HC), a TRPV4 channel antagonist, on change in tone (left panel) and contribution to ACh-induced relaxation (right panel) using vessels obtained from both control (black) and ovx (grey) mice. B: Summarized results from studies using 300 nM GSK1016790, a TRPV4 channel agonist, on changes to vascular tension in the absence and presence of apamin (apa) and/or tram34 (tram). These studies were performed in the presence of L-NAME and indomethacin. Asterisk (*) denotes statistical significance (P<0.05, t-test).

Mentions: Previous studies have shown that endothelial TRPV4 channels provide Ca2+ activation of SK3 and IK1 channels [10], [28]. Thus, we examined whether the ovx-induced shift in IK1/SK3 channel contribution to EDH-mediated vasorelaxation would be reflected by changes in TRPV4 channel activity. We performed the same experiments but in the presence of both 100 µM L-NAME and 10 µM indomethacin to block NO and PGI2 pathways, respectively (Fig. 4). In this condition, EDH is the major contributor to vascular tone. Application of HC067047 (HC, 500 nM) to block TRPV4 channels modestly increased basal force (control: 6.6±1.1; ovx: 3.0±2.5; n = 8; P>0.05; Fig. 4A left) and reduced ACh-induced vasorelaxation (control: 11.5±3.1; ovx: 5.9±3.4; P>0.05; Fig. 4A right) in both groups, consistent with contribution of TRPV4 channel activity to vasorelaxation.


Ovariectomy-induced reductions in endothelial SK3 channel activity and endothelium-dependent vasorelaxation in murine mesenteric arteries.

Yap FC, Taylor MS, Lin MT - PLoS ONE (2014)

IK1 channel activity mediates TRPV4-induced vasorelaxation in ovx vessels.A: Summarized results from studies using 500 nM HC067047 (HC), a TRPV4 channel antagonist, on change in tone (left panel) and contribution to ACh-induced relaxation (right panel) using vessels obtained from both control (black) and ovx (grey) mice. B: Summarized results from studies using 300 nM GSK1016790, a TRPV4 channel agonist, on changes to vascular tension in the absence and presence of apamin (apa) and/or tram34 (tram). These studies were performed in the presence of L-NAME and indomethacin. Asterisk (*) denotes statistical significance (P<0.05, t-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126749&req=5

pone-0104686-g004: IK1 channel activity mediates TRPV4-induced vasorelaxation in ovx vessels.A: Summarized results from studies using 500 nM HC067047 (HC), a TRPV4 channel antagonist, on change in tone (left panel) and contribution to ACh-induced relaxation (right panel) using vessels obtained from both control (black) and ovx (grey) mice. B: Summarized results from studies using 300 nM GSK1016790, a TRPV4 channel agonist, on changes to vascular tension in the absence and presence of apamin (apa) and/or tram34 (tram). These studies were performed in the presence of L-NAME and indomethacin. Asterisk (*) denotes statistical significance (P<0.05, t-test).
Mentions: Previous studies have shown that endothelial TRPV4 channels provide Ca2+ activation of SK3 and IK1 channels [10], [28]. Thus, we examined whether the ovx-induced shift in IK1/SK3 channel contribution to EDH-mediated vasorelaxation would be reflected by changes in TRPV4 channel activity. We performed the same experiments but in the presence of both 100 µM L-NAME and 10 µM indomethacin to block NO and PGI2 pathways, respectively (Fig. 4). In this condition, EDH is the major contributor to vascular tone. Application of HC067047 (HC, 500 nM) to block TRPV4 channels modestly increased basal force (control: 6.6±1.1; ovx: 3.0±2.5; n = 8; P>0.05; Fig. 4A left) and reduced ACh-induced vasorelaxation (control: 11.5±3.1; ovx: 5.9±3.4; P>0.05; Fig. 4A right) in both groups, consistent with contribution of TRPV4 channel activity to vasorelaxation.

Bottom Line: The results from functional studies using isolated murine mesenteric arteries show that ovx reduces ACh-induced endothelium-dependent vasodilation due to decreased EDH and NO contributions, although the contribution of PGI2 is upregulated.The decreased EDH-mediated vasorelaxation in ovx vessels is due to reduced SK3 channel contribution to the pathway.Further, whole-cell recordings using dispersed endothelial cells also show reduced SK3 current density in ovx endothelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of South Alabama, Mobile, Alabama, United States of America.

ABSTRACT
Mesenteric artery endothelium expresses both small (SK3)- and intermediate (IK1)-conductance Ca(2+)-activated K(+) (KCa) channels whose activity modulates vascular tone via endothelium-dependent hyperpolarization (EDH). Two other major endothelium-dependent vasodilation pathways utilize nitric oxide (NO) and prostacyclin (PGI2). To examine how ovariectomy (ovx) affects the basal activity and acetylcholine (ACh)-induced activity of each of these three pathways to vasorelaxation, we used wire myograph and electrophysiological recordings. The results from functional studies using isolated murine mesenteric arteries show that ovx reduces ACh-induced endothelium-dependent vasodilation due to decreased EDH and NO contributions, although the contribution of PGI2 is upregulated. Both endothelial SK3 and IK1 channels are functionally coupled to TRPV4 (transient receptor potential, vanilloid type 4) channels: the activation of TRPV4 channels activates SK3 and IK1 channels, leading to EDH-mediated vascular relaxation. The decreased EDH-mediated vasorelaxation in ovx vessels is due to reduced SK3 channel contribution to the pathway. Further, whole-cell recordings using dispersed endothelial cells also show reduced SK3 current density in ovx endothelial cells. Consequently, activation of TRPV4 channels induces smaller changes in whole-cell current density. Thus, ovariectomy leads to a reduction in endothelial SK3 channel activity thereby reducing the SK3 contribution to EDH vasorelaxation.

Show MeSH
Related in: MedlinePlus