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C-Kit deficiency impairs nitric oxide signaling in smooth muscle cells.

ABSTRACT: INTRODUCTION:Receptor tyrosine kinases have been implicated in various vascular remodeling processes and cardiovascular disease. However, their role in the regulation of vascular tone is poorly understood. Herein, we evaluate the contribution of c-Kit signaling to vasoactive responses. METHODS:The vascular reactivity of mesenteric arteries was assessed under isobaric conditions in c-Kit deficient (KitW/W-v) and littermate control mice (Kit+/+) using pressure myography. Protein levels of soluble guanylyl cyclase beta 1 (sGC?1) were quantified by Western blot. Mean arterial pressure was measured after high salt (8% NaCl) diet treatment using the tail-cuff method. RESULTS:Smooth muscle cells (SMCs) from c-Kit deficient mice showed a 5-fold downregulation of sGC?1 compared to controls. Endothelium-dependent relaxation of mesenteric arteries demonstrated a predominance of prostanoid vs. nitric oxide (NO) signaling in both animal groups. The dependence on prostanoid-induced dilation was higher in c-Kit mutant mice than in controls, as indicated by a significant impairment in vasorelaxation with indomethacin with respect to the latter. Endothelium-independent relaxation showed significant dysfunction of NO signaling in c-Kit deficient SMCs compared to controls. Mesenteric artery dilation was rescued by addition of a cGMP analog, but not with a NO donor, indicating a deficiency in cGMP production in c-Kit deficient SMCs. Finally, c-Kit deficient mice developed higher blood pressure on an 8% NaCl diet compared to their control littermates. CONCLUSION:c-Kit deficiency inhibits NO signaling in SMCs. The existence of this c-Kit/sGC signaling axis may be relevant for vascular reactivity and remodeling.

SUBMITTER: Hernandez DR

PROVIDER: S-EPMC6732002 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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c-Kit deficiency impairs nitric oxide signaling in smooth muscle cells.

Hernandez Diana R DR Rojas Miguel G MG Martinez Laisel L Rodriguez Boris L BL Zigmond Zachary M ZM Vazquez-Padron Roberto I RI Lassance-Soares Roberta M RM

Biochemical and biophysical research communications 20190812 2

<h4>Introduction</h4>Receptor tyrosine kinases have been implicated in various vascular remodeling processes and cardiovascular disease. However, their role in the regulation of vascular tone is poorly understood. Herein, we evaluate the contribution of c-Kit signaling to vasoactive responses.<h4>Methods</h4>The vascular reactivity of mesenteric arteries was assessed under isobaric conditions in c-Kit deficient (Kit<sup>W/W-v</sup>) and littermate control mice (Kit<sup>+/+</sup>) using pressure ...[more]

PMID: 31416613

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Project description:Nitric oxide (NO), generated in skeletal muscle mostly by the neuronal NO synthases (nNOS?), has profound effects on both mitochondrial bioenergetics and muscle development and function. The importance of NO for muscle repair emerges from the observation that nNOS signalling is defective in many genetically diverse skeletal muscle diseases in which muscle repair is dysregulated. How the effects of NO/nNOS? on mitochondria impact on muscle function, however, has not been investigated yet.In this study we have examined the relationship between the NO system, mitochondrial structure/activity and skeletal muscle phenotype/growth/functions using a mouse model in which nNOS? is absent. Also, NO-induced effects and the NO pathway were dissected in myogenic precursor cells.We show that nNOS? deficiency in mouse skeletal muscle leads to altered mitochondrial bioenergetics and network remodelling, and increased mitochondrial unfolded protein response (UPR(mt)) and autophagy. The absence of nNOS? is also accompanied by an altered mitochondrial homeostasis in myogenic precursor cells with a decrease in the number of myonuclei per fibre and impaired muscle development at early stages of perinatal growth. No alterations were observed, however, in the overall resting muscle structure, apart from a reduced specific muscle mass and cross sectional areas of the myofibres. Investigating the molecular mechanisms we found that nNOS? deficiency was associated with an inhibition of the Akt-mammalian target of rapamycin pathway. Concomitantly, the Akt-FoxO3-mitochondrial E3 ubiquitin protein ligase 1 (Mul-1) axis was also dysregulated. In particular, inhibition of nNOS/NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent-protein kinases induced the transcriptional activity of FoxO3 and increased Mul-1 expression. nNOS? deficiency was also accompanied by functional changes in muscle with reduced muscle force, decreased resistance to fatigue and increased degeneration/damage post-exercise.Our results indicate that nNOS?/NO is required to regulate key homeostatic mechanisms in skeletal muscle, namely mitochondrial bioenergetics and network remodelling, UPR(mt) and autophagy. These events are likely associated with nNOS?-dependent impairments of muscle fibre growth resulting in a deficit of muscle performance.

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C-Kit deficiency impairs nitric oxide signaling in smooth muscle cells.

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c-Kit deficiency impairs nitric oxide signaling in smooth muscle cells.

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