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. 2011 Aug;18(6):452-62.
doi: 10.1111/j.1549-8719.2011.00106.x.

P-selectin mediates the microvascular dysfunction associated with persistent cytomegalovirus infection in normocholesterolemic and hypercholesterolemic mice

Evgeny Senchenkov  1 , Mikhail V Khoretonenko, Igor L Leskov, Dmitry V Ostanin, Karen Y Stokes
Affiliations

P-selectin mediates the microvascular dysfunction associated with persistent cytomegalovirus infection in normocholesterolemic and hypercholesterolemic mice

Evgeny Senchenkov et al. Microcirculation. 2011 Aug.

Abstract

Objective: Cytomegalovirus has been implicated in cardiovascular disease, possibly through the induction of inflammatory processes. P-selectin and L-selectin are adhesion molecules that mediate early microvascular responses to inflammatory stimuli. This study examined the role of these selectins in the microvascular dysfunction that occurs during persistent CMV infection.

Methods: C57Bl/6, P- or L-selectin-deficient mice were mock-inoculated or infected with murine CMV, and five weeks later placed on normal diet or high cholesterol diet for six weeks. P-selectin expression was measured or intravital microscopy was performed to determine arteriolar vasodilation and venular blood cell recruitment.

Results: P-selectin expression was significantly increased in the heart, lung, and spleen of mCMV-ND, but not mCMV-HC C57Bl/6. mCMV-ND and mCMV-HC exhibited impaired arteriolar function, which was reversed by treatment with an anti-P-selectin antibody, but not L-selectin deficiency. mCMV-HC also showed elevated leukocyte and platelet recruitment. P-selectin inhibition abrogated, whereas L-selectin deficiency partially reduced these responses.

Conclusions: We provide the first evidence for P-selectin upregulation by persistent mCMV infection and implicate this adhesion molecule in the associated arteriolar dysfunction. P-selectin, and to a lesser extent L-selectin, mediates the leukocyte and platelet recruitment induced by CMV infection combined with hypercholesterolemia.

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Figures

Figure 1
Figure 1
P-selectin expression, as measured by DRL, in (A) heart, (B) lung, (C) spleen and (D) cremaster muscle of WT mice 11 wks after exposure to mock inoculum or mCMV. Mice were either maintained on ND, or placed on HC at 5 wks p.i. for 6 wks. * P<0.05 vs. Mock-ND; ^ P<0.05 vs. Mock-HC; # P<0.05 vs. mCMV-ND; ## P<0.01 vs. mCMV-ND.
Figure 2
Figure 2
P-selectin expression in (A) skeletal muscle, (B) small bowel, (C) perigonadal fat, and (D) aorta, of WT mice 11 wks after injection with mock inoculum or mCMV. Mice were maintained on ND or changed to HC at 5 wks p.i. until P-selectin assessment. * P<0.05 vs. Mock-ND; ** P<0.01 vs. Mock-ND; # P<0.05 vs. mCMV-ND; ## P<0.01 vs. mCMV-ND.
Figure 3
Figure 3
% change in diameter from baseline in arterioles in responses to the endothelium-dependent vasodilator, acetylcholine (ACh) (A) or the endothelium-independent vasodilator, papaverine (papav) (B). The ratio between papav and ACh responses is depicted in panel C. WT, P-sel−/− or L-sel−/− mice received mock inoculum or mCMV, and were either kept on ND, or switched to HC at 5 wks p.i., until observation at 11 wks p.i. Separate WT mCMV groups were treated with anti-P-selectin antibody (+P-sel Ab) or an isotype-matched control antibody (+P-sel iso Ab) 24 h prior to the experiment. * P<0.05 vs. both WT Mock groups; ** P<0.005 vs. both WT Mock groups; # P<0.005 vs. WT mCMV-ND and WT mCMV-ND+P-sel iso Ab; ^ P<0.005 vs. WT mCMV-HC; ^^ P<0.0005 vs. WT mCMV-HC; † P<0.01 vs. WT mCMV-HC+P-sel iso Ab; § P<0.005 vs. L-sel−/− Mock-ND.
Figure 4
Figure 4
The number of adherent leukocytes in postcapillary venules (A) and leukocytes emigrated into the surrounding interstitium (B) in the cremaster muscle of WT, P-sel−/− or L-sel−/− mice exposed to mock inoculum or mCMV. Mice remained on ND or were changed to HC at 5 wks p.i. until observation at 11 wks p.i. Separate WT mCMV groups received anti-P-selectin antibody (+P-sel Ab) or an isotype-matched control antibody (+P-sel iso Ab) 24 h prior to observation. * P<0.05 vs. both WT Mock groups and mCMV-ND; ** P<0.005 vs. both WT Mock groups and mCMV-ND; # P<0.01 vs. WT mCMV-HC; ## P<0.0001 vs. WT mCMV-HC; ^ P<0.0005 vs. WT mCMV-HC+P-sel iso Ab.
Figure 5
Figure 5
Leukocyte rolling flux (# of leukocytes rolling past a specific point per minute) (A), and leukocyte rolling velocity (B) in postcapillary venules of WT, P-sel−/− or L-sel−/− mice injected with mock inoculum and maintained on ND or infected with mCMV and placed on HC at 5 wk p.i. Intravital microscopy observation of the venules was performed at 11 wks p.i. Only one out of ten mice had leukocytes that rolled for 100 μm in the P-sel Ab group, and could be considered for measurement of velocity. No leukocyte rolling was detected in the P-sel−/− mice (denoted by “0”). * P<0.05 vs. WT mCMV-HC; # P<0.005 vs. WT mCMV-HC+P-sel iso Ab.
Figure 6
Figure 6
Total adhesion (A), saltation (B) and firm adhesion (C) of exogenous platelets in postcapillary venules of WT, P-sel−/− or L-sel−/− mice receiving mock inoculum or mCMV, and maintained on ND or placed on HC at 5 wks p.i. All platelet donors matched recipients in terms of WT mouse strain, infection and diet, with the exception of the 7th bar, which represents platelets from P-sel−/− mCMV-HC donors observed in WT mCMV-HC recipients (WT mCMV-HC w/P-sel−/− pl). “0” denotes zero adhesion as measured in the mCMV-HC+P-sel Ab group. * P<0.05 vs. WT Mock-ND; ** P<0.005 vs. both WT Mock groups and WT mCMV-ND; # P<0.05 vs. mCMV-HC; ## P<0.005 vs. mCMV-HC; ^ P<0.01 vs. mCMV-HC+P-sel iso Ab.
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