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

Gloria E Hernandez,Peng Zhao,Feiyang Ma,Anna E Beaudin,Matthew J Flick,Reza Ardehali,Jocelynda Salvador,Christian J Kastrup,M Luisa Iruela-Arispe,Diego A López,Matteo Pellegrini,Jerry Leung,Lih Jiin Juang,Nadia B Firozabadi,Guadalupe Martinez

doi:10.1038/s44161-021-00006-4

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. These macrophages 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, such as 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 leads to thrombin-mediated endothelial cell contraction, progressive fibrin accumulation and formation of microthrombi that, once dislodged, cause blockade of vessels in several organs. Together the findings reveal that intravascular resident macrophages are essential to regulate thrombin activity and clear fibrin deposits in regions of disturbed blood flow.

Highlights

As a gatekeeper of cellular traffic between blood and tissues, the endothelium is well equipped to interact with hematopoietic cells
Our findings indicate that, while endothelial cells provide a non-thrombogenic surface, facilitating blood circulation in areas of disturbed flow, this function is challenged by the accumulation of fibrinogen and thrombin
The unusual feature that captured our attention was that seeding of this macrophage population occurred after birth; these cells displayed a unique topology in relation to the endothelium

Summary

Introduction

As a gatekeeper of cellular traffic between blood and tissues, the endothelium is well equipped to interact with hematopoietic cells. In addition to patrolling monocytes, myeloid cells with a highly dendritic appearance were described in the luminal aspect of the aorta, especially at sites prone to develop atherosclerosis, such as the aortic arch[13,14]. We show that the emergence of aortic myeloid cells is not pathologically induced; instead, it is developmentally triggered as part of natural hemodynamic changes at birth that result in localized disturbed flow dynamics. Genetic ablation of this aortic myeloid resident population promotes fibrin deposition and microthrombus formation, clarifying its function as a critical regulator of hemostasis

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