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Aortic intimal resident macrophages are essential for maintenance of the non-thrombogenic intravascular state.

ABSTRACT: Leukocytes and endothelial cells frequently cooperate to resolve inflammatory events. In most cases, these interactions are transient in nature and triggered by immunological insults. Here, we report that in areas of disturbed blood flow, aortic endothelial cells permanently and intimately associate with a population of specialized macrophages that are recruited at birth from the closing ductus arteriosus and share the luminal surface with the endothelium becoming interwoven in the tunica intima. Anatomical changes that affect hemodynamics, like in patent ductus arteriosus, alter macrophage seeding to coincide with regions of disturbed flow. Aortic resident macrophages expand in situ via direct cell renewal. Induced-depletion of intimal macrophages led to thrombin-mediated endothelial cell contraction, progressive fibrin accumulation and formation of microthrombi that, once dislodged, caused blockade of vessels in several organs. Together the findings revealed that intravascular resident macrophages are essential to regulate thrombin activity and clear fibrin deposits in regions of disturbed blood flow.

SUBMITTER: Hernandez GE

PROVIDER: S-EPMC9121812 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Aortic intimal resident macrophages are essential for maintenance of the non-thrombogenic intravascular state.

Hernandez Gloria E GE Ma Feiyang F Martinez Guadalupe G Firozabadi Nadia B NB Salvador Jocelynda J Juang Lih Jiin LJ Leung Jerry J Zhao Peng P López Diego A DA Ardehali Reza R Beaudin Anna E AE Kastrup Christian J CJ Pellegrini Matteo M Flick Matthew J MJ Iruela-Arispe M Luisa ML

Nature cardiovascular research 20220112 1

Leukocytes and endothelial cells frequently cooperate to resolve inflammatory events. In most cases, these interactions are transient in nature and triggered by immunological insults. Here, we report that in areas of disturbed blood flow, aortic endothelial cells permanently and intimately associate with a population of specialized macrophages that are recruited at birth from the closing ductus arteriosus and share the luminal surface with the endothelium becoming interwoven in the tunica intima ...[more]

PMID: 35599984

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Project description:Vascular endothelial and hematopoietic cells hold a close relationship that is initiated during development, but that continuously broadens to include new functions aimed at maintaining homeostasis in the adult organism. Here, we report on a population of aortic intimal resident macrophages (MacAIRs) that is a permanent feature of the inner vessel wall (tunica intima) of the aorta in regions of turbulent flow and that shares the luminal surface with the endothelium. MacAIRs were found to be transcriptionally distinct from other macrophages and closely associated with the endothelium in the absence of pathology. Lineage tracing analysis indicated that adult MacAIRs were derived from definitive hematopoietic lineage precursors that migrated from the ductus arteriosus seeding the aorta immediately post-birth in areas of turbulent flow including the lesser curvature of the aortic arch and branch openings. These aortic resident macrophages expanded via direct cell renewal and continued to grow in aged aortae to also populate regions of laminar flow. Binding of MacAIRs relied heavily on expression of endothelial ICAM that interacts with CD11c on macrophages. Genetic deletion of CD11c significantly impaired anchorage of MacAIRs to the endothelium. To clarify the biological significance of this population of macrophages, we used a dual diphtheria toxin induced-depletion system that efficiently eliminated MacAIRs in adult mice. Utilizing this model, we found that absence of MacAIRs led to progressive fibrin accumulation and formation of microclots that, once dislodged, can cause blockade of vessels and organ failure. In fact, 40% of the animals with genetic-mediated depletion of MacAIRs died within 2 weeks post-depletion suggesting that these macrophages were required to clear fibrin deposits in regions of turbulent blood flow. These findings advance our knowledge of how vascular endothelial cells profit from this unique interaction with macrophages to control hemostasis, prevent intravascular clotting, and ensure vascular health.

Dataset Information

Aortic intimal resident macrophages are essential for maintenance of the non-thrombogenic intravascular state.

Publications

Aortic intimal resident macrophages are essential for maintenance of the non-thrombogenic intravascular state.

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