Abstract 3154: Neonatal c-kit Mutant Mice Exhibit Decreased Susceptibility to Hypoxia-Induced Pulmonary Hypertension
Background: c-kit is a tyrosine kinase receptor which is involved in the regulation of cell survival and proliferation. Given, our previous data showing increased c-kit cells in the lungs of neonatal mice with chronic hypoxia (Hyp)-induced PH, we hypothesized that neonatal mice with defective c-kit receptors would have decreased susceptibility to chronic Hyp-induced PH.
Objective: To determine if neonatal c-kit mutant mice have decreased pulmonary vascular response to chronic Hyp.
Design/Methods: Neonatal c-kit mutant mice (WBB6F1- Kit W−v/+) and their congenic controls (n=22) were exposed to Hyp (FiO2=0.12) or normoxia (RA) for 2 wk. After set period, right ventricular systolic pressure (RVSP) and the ratio of the weight of the right ventricle to the left ventricle = septum (RV/LV=S) were measured. To further test our hypothesis, neonatal FVB/NJ mice (n=20) exposed to RA or Hyp for 2 wk were assigned to receive daily intra-peritoneal injections of saline (PL), or anti-c-kit-antibody (ACK2; 50 μg) from postnatal day 7–14. Morphometric determination of vessel muscularization was performed on pulmonary arterioles with an external diameter of 15–50μm. Data were analyzed by ANOVA.
Results: Exposure of neonatal c-kit mutant mice to Hyp resulted in a significantly lower RVSP (p<0.01), RV/LV+S (p<0.005) and pulmonary vascular remodeling (p<0.01), as compared to control Hyp mice. Moreover, administration of ACK2 to hypoxic mice resulted in a marked attenuation in RVSP (15±1 vs 28±4 vs 21±2; RA vs HypPL vs HypACK2; p<0.02), RV/LV+S, (p<0.01), pulmonary vascular remodeling (p<0.05) as well as a significant reduction in the percentage of pulmonary vascular proliferating cells.
Conclusions: Neonatal c-kit mutant mice have decreased susceptibility to PH. These findings suggest that intact c-kit signaling is crucial for the development of PH and thus inhibition of c-kit activity may be a novel strategy for the treatment of PH.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).