Chen, Wen and Oberwinkler, Heike and Werner, Franziska and Ganer, Birgit and Nakagawa, Hitoshi and Feil, Robert and Hofmann, Franz and Schlossmann, Jens and Dietrich, Alexander and Gudermann, Thomas and Nishida, Motohiro and Del Galdo, Sabrina and Wieland, Thomas and Kuhn, Michaela (2013) Atrial Natriuretic Peptide-Mediated Inhibition of Microcirculatory Endothelial Ca2+ and Permeability Response to Histamine Involves cGMP-Dependent Protein Kinase I and TRPC6 Channels. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 33 (9). pp. 2121-2129. ISSN 1079-5642,
Full text not available from this repository. (Request a copy)Abstract
Objective-Histamine increases microvascular endothelial leakage by activation of complex calcium-dependent and -independent signaling pathways. Atrial natriuretic peptide (ANP) via its cGMP-forming guanylyl cyclase-A (GC-A) receptor counteracts this response. Here, we characterized the molecular mechanisms underlying this interaction, especially the role of cGMP-dependent protein kinase I (cGKI). Approach and Results-We combined intravital microscopy studies of the mouse cremaster microcirculation with experiments in cultured microvascular human dermal endothelial cells. In wild-type mice, ANP had no direct effect on the extravasation of fluorescent dextran from postcapillary venules, but strongly reduced the histamine-provoked vascular leakage. This anti-inflammatory effect of ANP was abolished in mice with endothelial-restricted inactivation of GC-A or cGKI. Histamine-induced increases in endothelial [Ca2+](i) in vitro and of vascular leakage in vivo were markedly attenuated by the Ca2+-entry inhibitor SKF96365 and in mice with ablated transient receptor potential canonical (TRPC) 6 channels. Conversely, direct activation of TRPC6 with hyperforin replicated the hyperpermeability responses to histamine. ANP, via cGKI, stimulated the inhibitory phosphorylation of TRPC6 at position Thr(69) and prevented the hyperpermeability responses to hyperforin. Moreover, inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil prevented the edematic actions of histamine in wild types but not in mice with endothelial GC-A or cGKI deletion. Conclusions-ANP attenuates the inflammatory actions of histamine via endothelial GC-A/cGMP/cGKI signaling and inhibitory phosphorylation of TRPC6 channels. The therapeutic potential of this novel regulatory pathway is indicated by the observation that sildenafil improves systemic endothelial barrier functions by enhancing the endothelial effects of endogenous ANP.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GUANYLYL CYCLASE-A; NITRIC-OXIDE; MAST-CELLS; PLASMA-VOLUME; RECEPTOR; MUSCLE; MICE; ACTIVATION; PATHWAY; VIVO; atrial natriuretic factor; cyclic GMP; cyclic GMP dependent protein kinase I; endothelial cells; guanylyl cyclase A; TRPC6 channel |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 08:43 |
| Last Modified: | 02 Apr 2020 08:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/16161 |
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