Abstract 5536: Strain-dependent Susceptibility for Hypertension in Mice Resides in the Natural Killer Gene Complex

Abstract

Hypertension is accompanied by vascular remodeling and inflammation. We tested the hypothesis that the sensitivity to develop hypertension and vascular remodeling depends on the immunological background. Methods: Blood pressure, vascular remodeling and expression of inflammatory cytokines were determined in mice with a genetically determined difference in immune background: C57BL/6 mice and BALB/c mice; and additionally BALB.B6-Cmv1r mice, a congenic strain where the natural killer (NK) gene complex of C57BL/6 mice is introduced in BALB/c background. Mice were treated for 4 weeks with L-NAME (NG-nitro-L-arginine methyl ester). Systemic and local inflammatory responses were quantified in spleen and mesenteric arteries respectively. Results: L-NAME treatment induced a significant increase in mean arterial blood pressure in C57BL/6 mice, from 101±4 mmHg (n=7) to 154±5 mmHg (n=5, P<0.001). This was accompanied by a highly significant increase in vessel wall-to-lumen ratio, from 0.104±0.002 (n= 6) to 0.126±0.003 in L-NAME treated mice (n=6, P<0.001). In BALB/c mice the blood pressure (117±3 mmHg for untreated vs. 126±6 mmHg for L-NAME treated mice) and wall to lumen ratio (0.104±0.003 in untreated vs. 0.113±0.003 in L-NAME treated mice) were not altered after 4 weeks of L-NAME treatment. The congenic BALB.B6-Cmv1r mice showed a similar sensitivity to develop hypertension and vascular remodeling as C57Bl/6 mice: blood pressure increased from 111±11 mmHg to 155±7 mmHg (P<0.01). The wall to lumen ratio increased from 0.107±0.003 to 0.125±0.008 (P<0.05). Expression of inflammatory markers such as IFN γ , IL1, IL10 and CD68 (macrophages) was similar in C57BL/6 and BALB/c, with exception of CD11b, which increased in vessels of C57BL/6 mice only. Confocal microscopy showed that CD11b co-localized with NK1.1, and reflected the recruitment of natural killer cells in C57BL/6 mice. Conclusions: These data show that vascular remodeling and hypertension are strain dependent. We have identified the NK gene complex as important determinant in the genetically determined sensitivity to develop hypertension in mice.