Impact of cGMP generated by NO-sensitive guanylyl cyclases on vascular smooth muscle remodelling
Final Report Abstract
In the vasculature, the NO/cGMP signalling cascade has an established function in the regulation of smooth muscle tone but also has been proposed to affect smooth muscle cell proliferation. In these cells, most of the cGMP is formed by the guanylyl cyclase NO-GC1 which is stimulated (GC) by NO continuously produced in response to shear stress. We generated knockout (KO) mice deficient of the NO-GC1 isoform and showed that cGMP formation in response to NO is greatly reduced (about 90%) and vascular relaxation is attenuated. To study the role of NO/cGMP in smooth muscle proliferation, we induced proliferation in the NO- GC1 KO mice by applying the pro-proliferative Angiotensin (Ang II). Ang II-induced vascular remodelling was assessed as aortic medial area and did not differ between NO-GC1 KO and WT. Yet, the increase was more pronounced in NO-GC1 KO as the medial area of the non-treated KO mice was smaller. Therefore, AngII-induced remodelling has to be confirmed in a mouse model of acute i.e. inducible NO-GC1 inactivation. Smooth muscle cell proliferation was enhanced by the Ang II treatment as detected by the DNA marker BrdU. Yet, the increase in number of BrdU-labeled cells did not differ between WT and KO aortas. Remarkably, in Ang II-treated KO aortas the total number of SMCs was increased whereas the number remained unchanged in Ang II-treated WT indicating a role of cGMP in cell cycle arrest. Enhanced proliferation of NO-GC1-deficient SMCs was also observed in primary VSMCs under FCS-stimulating conditions, ex vivo. However, attempts to attenuate proliferation using cGMP-increasing agents or cGMP analogous in WT and KO cells failed to demonstrate a clear contribution of NO/cGMP signaling in cell proliferation under these conditions. Taken together, this work indicates that attenuation of the NO/cGMP pathway in vivo enhances smooth muscle cell proliferation and suggests an anti-proliferative role of cGMP by the cell cycle progression.
Publications
- Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice. J Pharmacol Exp Ther. 356:191-199; 2016
Broekmans K, Stegbauer J, Potthoff SA, Russwurm M, Koesling D, Mergia E
(See online at https://doi.org/10.1124/jpet.115.227728) - Proatherosclerotic Effect of the α1- Subunit of Soluble Guanylyl Cyclase by Promoting Smooth Muscle Phenotypic Switching. Am J Pathol. 186:2220-2231; 2016
Segura-Puimedon M, Mergia E, Al-Hasani J, Aherrahrou R, Stoelting S, Kremer F, Freyer J, Koesling D, Erdmann J, Schunkert H, de Wit C, Aherrahrou Z
(See online at https://doi.org/10.1016/j.ajpath.2016.04.010)
