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

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.

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

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.