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. 2014 Dec 15;307(12):H1745-53.
doi: 10.1152/ajpheart.00201.2014. Epub 2014 Oct 17.

Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction

Mikhail V Khoretonenko  1 , Jerry L Brunson  1 , Evgeny Senchenkov  2 , Igor L Leskov  2 , Christian R Marks  2 , Karen Y Stokes  3
Affiliations

Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction

Mikhail V Khoretonenko et al. Am J Physiol Heart Circ Physiol. .

Abstract

Cytomegalovirus (CMV) infects a majority of the population worldwide. It has been implicated in cardiovascular disease, induces microvascular dysfunction, and synergizes with hypercholesterolemia to promote leukocyte and platelet recruitment in venules. Although platelets and platelet-associated P-selectin contribute to cardiovascular disease inflammation, their role in CMV-induced vascular responses is unknown. We assessed the role of platelets in CMV-induced microvascular dysfunction by depleting platelets and developing bone marrow chimeric mice deficient in platelet P-selectin. Wild-type and chimeric mice received mock or murine (m)CMV intraperitoneally. Five weeks later, some mice were switched to a high-cholesterol diet (HC) to investigate the synergism between mCMV and HC. Arteriolar vasodilation and recruitment of leukocytes and donor platelets in venules were measured at 11wk. mCMV with or without HC caused significant endothelial dysfunction in arterioles. Platelet depletion restored normal vasodilation in mCMV-HC but not mCMV-ND mice, whereas protection was seen in both groups for platelet P-selectin chimeras. Only mCMV + HC elevated leukocyte and platelet recruitment in venules. Leukocyte adhesion was reduced to mock levels by acute platelet depletion but was only partially decreased in platelet P-selectin chimeras. Platelets from mCMV-HC mice and, to a lesser extent, mCMV-ND but not mock-HC mice showed significant adhesion in mCMV-HC recipients. Our findings implicate a role for platelets, acting through P-selectin, in CMV-induced arteriolar dysfunction and suggest that the addition of HC leads to a platelet-dependent, inflammatory infiltrate that is only partly platelet P-selectin dependent. CMV appeared to have a stronger activating influence than HC on platelets and may represent an additional therapeutic target in vulnerable patients.

Keywords: arteriolar dilation; hypercholesterolemia; leukocyte adhesion; microvasculature; platelets.

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Figures

Fig. 1.
Fig. 1.
Changes in arteriolar diameter in response to ACh (A and B) or papaverine (C) at 11 wk postinfection in mice injected with mock inoculum (mock) or murine cytomegalovirus (mCMV) and maintained on a normal diet (ND) or placed on a high-cholesterol diet (HC) at 5 wk postinfection. Some mice received rabbit serum (RS) or anti-platelet serum (APS) 24 h before observations. ^P ≤ 0.0001, mock-ND vs. all other mCMV groups; *P < 0.001 vs. mock-ND and mock-HC groups; #P < 0.0005 vs. other mCMV-HC groups.
Fig. 2.
Fig. 2.
Arteriolar vasodilation in response to ACh (A) or papaverine (B) in wild-type (WT), control chimeric (WT → WT Chim), or P-selectin chimeric (P-sel−/− → WT Chim) mice 11 wk after injection with mock inoculum or mCMV. Some mice were placed on HC at 5 wk postinfection. *P < 0.0001 vs. WT and WT-WT mock-ND groups; #P < 0.001 vs. other mCMV-ND groups; ^P < 0.0001 vs. other mCMV-HC groups.
Fig. 3.
Fig. 3.
Adherent leukocytes in postcapillary venules (A), emigrated leukocytes in the surrounding tissue (B), and rolling leukocytes in venules (C) of mice 11 wk after they received mock inoculum or mCMV and maintained on ND or placed on HC at 5 wk postinfection. Some mice were treated with RS or APS at 24 h before observations. *P < 0.005 vs. mock-ND, mock-HC, and mCMV-ND groups; #P < 0.0001 vs. other mCMV-HC groups.
Fig. 4.
Fig. 4.
Leukocyte adhesion in postcapillary venules (A), emigration into the interstitium (B), and rolling in venules (C) of WT, WT → WT Chim, and P-sel−/− → WT Chim mice 11 wk after injection with mock inoculum or mCMV. Some mCMV mice were placed on HC at 5 wk postinfection. *P < 0.005 vs. both mock-ND groups; #P < 0.0005 vs. the WT mCMV-HC group; ^P < 0.005 vs. the WT→WT Chim mCMV-HC group.
Fig. 5.
Fig. 5.
Adhesion of exogenous platelets (Pl) in postcapillary venules of matched (arrows) or mismatched recipients. Mice were injected with mock inoculum or mCMV, and, 5 wk later, some mice were placed on HC, whereas others were kept on ND. Observations were made at 11 wk postinfection. *P < 0.0005 vs. the mock-ND + mock-ND Pl group; #P < 0.0001 vs. all other groups.
Fig. 6.
Fig. 6.
Measurements of mCMV remaining in tubes containing virus or water as a control (input) or tubes containing virus only, platelets only, platelets + virus, or platelets + virus followed by treatment with proteinase K (adsorbed/bound). All of the adsorbed/bound tubes were washed to remove unbound or nonadsorbed virus before detection of viral DNA was performed. Data are expressed as percentages of input virus remaining based on the tube containing undiluted virus and not washed before detection. “0” denotes no signal detected.
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