UCLA

Despite advances in our understanding of cardiovascular risk factors, cardiovascular disease (CVD) continues to be the leading cause of mortality worldwide. The underlying pathology involved in many forms of CVD is atherosclerosis, a condition characterized by lipid deposition and chronic inflammation within the arterial wall of large blood vessels. The aorta is the largest artery of the body and subjected to significant physical forces due to the pressure of blood emanating from the heat. In this manner, distinct areas of the aorta are subjected to oscillatory, laminar, disturbed, and pulsatile flow due to their shape and proximity to the heart. Regions that experience oscillatory or “disturbed” blood flow are prone to developing atherosclerotic plaques whereas regions that experience uniform laminar flow are athero-protected. Further understanding of how different flow dynamics impact the tunica intima during homeostasis will help clarify the differential impact of distinct types of physiological shear stresses and the unique region-specific susceptibilities to disease development. Here, we show that the closure of the ductus arteriosus immediately post-birth initiates drastic hemodynamic changes in the aorta. Using single-cell RNA-sequencing, we found that the closure of the ductus arteriosus requires vimentin, the most abundant intermediate filament in vascular cells. Deletion of vimentin in mice caused patent ductus arteriosus, a congenital heart defect where the ductus fails to close. Additionally, we identified a tissue-resident macrophage population that is not pathologically induced, instead it is developmentally programmed to cope with the natural hemodynamic changes at birth that result in localized disturbed flow dynamics. This aortic intima-resident macrophage (MacAIR) population shares the luminal surface with the endothelium becoming interwoven in the tunica intima. Moreover, we found that MacAIRs are essential to regulate thrombin activity and clear fibrin deposits in regions of turbulent blood flow. Infection with SARS-Cov-2 also promoted rapid loss of intimal macrophages and robust accumulation of intravascular fibrin on the surface of the endothelium in infected rhesus macaque. These findings advance our knowledge of how vascular endothelial cells profit from this unique interaction with macrophages to preserve a non-thrombogenic surface, prevent intravascular clotting, and ensure vascular health.