Monocyte-platelet aggregates: bridging inflammaging and peripheral artery disease
Description: The entire vasculature is affected by aging. Evidence suggests that chronic inflammation in elders (inflammaging) contributes to the atherosclerosis of coronary and carotid arteries. In peripheral artery disease (PAD), atherosclerosis can lead to the occlusion of peripheral arteries impeding blood flow to the lower extremities. However, the mechanisms underlying how systemic inflammatory signals contribute to peripheral vascular damage are poorly defined. PAD severely affects the aged population with a prevalence of 10% > 65 years. It is often underdiagnosed, poorly medically managed, with high morbidity and mortality, especially in the setting of critical limb ischemia (CLI), a severe end-stage PAD characterized by ischemic pain and gangrene. CLI often requires amputation to limit necrosis of the leg. There are major knowledge gaps in the mechanisms associating aging and PAD, hindering the development of focused therapy. We recently demonstrated that increased circulating monocyte-platelets aggregates (MPA) were associated with patients with PAD and that MRP14 mediated platelet-monocyte interaction in MPA. In this proposal, we postulate that MPA are a hallmark of vascular inflammaging, bridging systemic age-related inflammation to the peripheral vascular tissue by increasing the recruitment of monocytes to the vascular wall. The rationale is based on new data showing that MPA linearly increase with age in humans and similarly in aged mice. Notably, transendothelial migration of MPA increased compared to monocytes alone, consistent with increased macrophage clusters in single-cell RNA sequencing of ischemic muscles in mice. Chemotactic signals increased in aged murine arteries suggesting synergistic effect in recruitment of MPA into the peripheral vasculature. In our specific aims, we provide novel mechanistic insights of how MRP14 regulates MPA migration and illuminate its role in a model of CLI in aged mice. We will track the biodynamics of platelet/monocyte interaction in the living animal by two-photon live microscopy of the vascular tissue. Finally, we will impair MPA formation by interference with Mrp14 and investigate the impact on CLI. The proposed research is innovative and provocative as we investigate MPA as a pathological culprit of CLI in inflammaging, an unexamined mechanism in PAD. We anticipate that our results will provide MRP14 as amenable target for the development of promising therapeutic strategies in aged and high-risk PAD patients.
Funder: American Heart Association
Amount: $160,300
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2022-01-01
End date: 2023-12-31
Investigator: Michele Silvestro (lead)
Institutions: New York University, NYU Grossman School of Medicine
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Funded outputs count: 3
Funder award ID: 907602
OpenAlex ID: G138415588