D. R. Hernandez1, L. Song1, Z. M. Zigmond1, Y. Wei1, L. Martinez1, R. M. Lassance-Soares1, R. I. Vazquez-Padron1 1University Of Miami,Surgery,Miami, FL, USA
Introduction:
The 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.
Methods:
Female 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).
Results:
The 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.
Conclusion:
These 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.