title: Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction.
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.
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Khoretonenko
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Brunson
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
authors.forename: Evgeny
authors.initials: E
authors.lastname: Senchenkov
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
authors.forename: Igor L
authors.initials: IL
authors.lastname: Leskov
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marks
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center, Shreveport, Louisiana kstoke@lsuhsc.edu.
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D002784:Cholesterol / Q000494:pharmacology; D003586:Cytomegalovirus Infections / Q000378:metabolism / Q000503:physiopathology*; D059305:Diet, High-Fat; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology* / Q000821:virology; D018146:Muromegalovirus / Q000472:pathogenicity; D019007:P-Selectin / Q000378:metabolism*; D014664:Vasodilation
chemical_list: D019007:P-Selectin; D002784:Cholesterol
keywords: arteriolar dilation; hypercholesterolemia; leukocyte adhesion; microvasculature; platelets