Abstract
Transient receptor potential canonical type 3 (TRPC3) channels are non-selective cation channels and regulate intracellular Ca2+ concentration. We examined the role of TRPC3 channels in agonist-, membrane depolarization (high K+)-, and mechanical (pressure)-induced vasoconstriction and vasorelaxation in mouse mesenteric arteries. Vasoconstriction and vasorelaxation of endothelial cells intact mesenteric arteries were measured in TRPC3 wild-type (WT) and knockout (KO) mice. Calcium concentration ([Ca2+]) was measured in isolated arteries from TRPC3 WT and KO mice as well as in the mouse endothelial cell line bEnd.3. Nitric oxide (NO) production and nitrate/nitrite concentrations were also measured in TRPC3 WT and KO mice. Phenylephrine-induced vasoconstriction was reduced in TRPC3 KO mice when compared to that of WT mice, but neither high K+- nor pressure-induced vasoconstriction was altered in TRPC3 KO mice. Acetylcholine-induced vasorelaxation was inhibited in TRPC3 KO mice and by the selective TRPC3 blocker pyrazole-3. Acetylcholine blocked the phenylephrine-induced increase in Ca2+ ratio and then relaxation in TRPC3 WT mice but had little effect on those outcomes in KO mice. Acetylcholine evoked a Ca2+ increase in endothelial cells, which was inhibited by pyrazole-3. Acetylcholine induced increased NO release in TRPC3 WT mice, but not in KO mice. Acetylcholine also increased the nitrate/nitrite concentration in TRPC3 WT mice, but not in KO mice. The present study directly demonstrated that the TRPC3 channel is involved in agonist-induced vasoconstriction and plays important role in NO-mediated vasorelaxation of intact mesenteric arteries.
Highlights
Changes in intracellular calcium concentration ([Ca2+]i) lead to diverse cellular responses, including vasoconstriction and release of vasodilators such as nitric oxide (NO) from endothelial cells (ECs)
We demonstrated that phenylephrine-induced vasoconstriction is decreased in TRPC3 KO mice when compared to that of WT mice, but neither membrane depolarization- nor mechanical-induced vasoconstriction were altered in TRPC3 KO mice
Endothelial TRPC3 contributes to endothelial NO release and subsequent endothelium-dependent vasorelaxation, which was evidenced as follows: (1) acetylcholineinduced vasorelaxation was inhibited in TRPC3 KO mice and by the selective TRPC3 blocker, pyrazole-3; (2) acetylcholine inhibited the phenylephrine-induced increase in [Ca2+]i ratio and subsequent relaxation in vessels from TRPC3 WT mice, but had little effect on those parameters in KO mice; (3) acetylcholine induced increases in [Ca2+]i in endothelial cells, which was inhibited by pyrazaole-3; (4) NO was released from mesenteric artery segments from WT mice in response to acetylcholine, but not from vessels from KO mice
Summary
Changes in intracellular calcium concentration ([Ca2+]i) lead to diverse cellular responses, including vasoconstriction and release of vasodilators such as nitric oxide (NO) from endothelial cells (ECs). Vascular contractility is primarily mediated by [Ca2+]i increase in response to agonists or mechanical stimulation [1]. The elevation in [Ca2+]i results in activation of the Ca2+/calmodulin-dependent enzyme myosin light chain kinase and the subsequent phosphorylation of regulatory myosin light chains (MLC20). This increased MLC20 phosphorylation enhances actomyosin ATPase activity and induces vascular contraction [2]. ECs produce and release vasoactive substances, such as nitric oxide (NO), to regulate vascular contractility. The elevation of [Ca2+]i in ECs activates nitric oxide synthase (NOS) via the Ca2+/calmodulin complex, which catalyzes the production of NO [3,4]. In non-excitable ECs, the increase in [Ca2+]i mainly depends on Ca2+ influx through store-operated Ca2+ channels and non-selective Ca2+ channels [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
