The role of c‐Kit/sGC signaling axis in vascular reactivity and hypertension

Abstract

A. IntroductionThe receptor tyrosine kinase c‐Kit has been recently found to have a role in vasculoprotection. Genetic deletion of c‐Kit in smooth muscle cells increases aortic plaque accumulation and atherosclerosis burden in conditional hyperlipidemic mice. The present study tests whether a c‐Kit deficiency in mutant mice (KitW/Wv) leads to hypertension and impaired vascular relaxation.B. MethodsFemale and male c‐Kit mutant (KitW/Wv) and littermate (Kit+/+) control mice were commercially available (Jackson lab). Blood pressure was determined in conscious mice using the tail‐cuff method. The first‐order branch of mesenteric artery was mounted into a pressure myograph (DMT, Aarhus, Denmark) to assess endothelium‐dependent and ‐independent vasoreactivity under isobaric conditions. A search for differentially expressed genes between c‐Kit mutant and control SMC was performed using the Mouse MI‐Ready microarray (Ocean Ridge Biosciences).C. ResultsThe deficiency of c‐Kit causes hypertension in mutant mice with respect to their control littermates (mean arterial pressure: 137.5 ± 5.0 vs. 113.06 ± 0.0, p=0.007). Acetylcholine (ACh) induced a concentration‐dependent relaxation of norepinephrine pre‐contracted vessels in both mutant and littermate mice. The Cox inhibitor indomethacin compromised ACh‐induced vasorelaxation only in c‐Kit deficient vessels but not in those from control mice, which highlighted the importance of endothelium‐derived prostaglandins for vasorelaxation in the absence of c‐Kit. Conversely, arteries of mutant mice were poor responders to a NO agonist (SNP). The secondary messenger, cyclic guanosine monophosphate, vasodilated both types of vessels in a similar manner, which indicated that defective NO activity in mutants was due to deficiencies in soluble guanylyl cyclase (sGC) or NO synthesis. A significant downregulation of smooth muscle sGC beta 1 subunit was further found in c‐Kit mutant cells using transcriptomics analysis.D. ConclusionThese results suggest the existence of a novel c‐Kit/sGC signaling axis in SMC that may be relevant for the control of vascular reactivity and hypertension.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.