This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Subproject #5: The Role of Platelets in Cytomegalovirus-Induced Inflammatory Disease Karen Y. Stokes Inflammation is a key component of cardiovascular disease, and it is recognized that platelets actively participate in the inflammatory responses to different cardiovascular risk factors. It is recognized that platelets actively participate in the inflammatory responses to different cardiovascular risk factors. Cytomegalovirus (CMV) is a cardiovascular risk factor that employs inflammatory mechanisms in order to disseminate and survive, this being a potential link between CMV and cardiovascular disease. In isolated cells, CMV can also induce platelet activation and adhesion however the role of platelets in CMV-induced inflammation remains unclear. We have a murine CMV (mCMV) model in which we can monitor responses of small vessels to infection, and have observed that mCMV infection promotes vessel dysfunction in arterioles, and with the introduction of hypercholesterolemia also induces an inflammatory and thrombogenic phenotype in venules. We hypothesize that platelets mediate CMV-induced microvascular inflammatory responses through interactions with (and activation of) other cells types, and that hypercholesterolemia exaggerates these responses. We will employ mutant mice, and antibodies to deplete platelets or block platelet surface receptors/counter-receptors, to test our hypothesis in our mCMV model. Our initial findings show that, regardless of diet, microvascular responses during CMV infection are dependent on P-selection, an adhesion molecule upregulated on platelets during CMV infection. Short-term depletion of platelets partially protects against CMV-induced arteriolar dysfunction and the accompanying venular inflammation during CMV infection in high cholesterol subjects. This proposal should provide novel insights into the thrombogenic potential of CMV and how it synergizes with other risk factors to exacerbate platelet activation, and therefore may reveal a target for early therapeutic intervention against cardiovascular disease.
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