Establishing a foundation for COVID-19 and vascular pathology

The vascular system
The vascular system also referred to as the circulatory system or vascular tree carries blood, oxygen and essential elements to all metabolically active tissues and organs of the body and carries waste materials and by-products away. There are five distinct components of the circulatory system: arteries and arterioles (arterial system), veins and venules (venous system) and capillaries (microvascular system) that link arterioles and venules. The dimensions of blood vessels vary by an order of several thousand-fold with capillaries as small as 10 µm to the aorta of 25 mm (Fig. 1).
Fig. 1 The circulatory system consists of the heart and large, medium and small arteries (arterioles), capillaries, small veins (venules, sinusoids) and large veins. Normal function depends on the flow of blood (and nutrients) to and from vital organs; however, the microvessels (arterioles, capillaries and venules) are responsible for vascular tone, homeostasis and tissue perfusion. From
Endothelial cells respond to injury in several stages (reviewed in Abraham). While there may be injurious agent-specific responses, in a majority of cases the initial event is triggered by infection (viral, bacterial), oxidative stress, hypoxia, turbulent blood flow and shear stress, environmental toxins and circulating elements that follow tissue injury with the release of cell-free nucleic acids, histones, chemokines, cytokines and damage-associated proteins.
The two-level response to endothelial cell injury includes an initial rapid response and a slower phenotypic response (reviewed in Abraham) [1]. Briefly, the initial response causes sudden changes in endothelial cell protective or integrity proteins, including nitric oxide, prostaglandins, endothelins, von Willebrand factor (VWF) and tissue plasminogen activator. The slower phenotype response reflects structural changes of endothelial cell topography, cell orientation, basement membranes and surrounding smooth muscle cells. In addition to the extent of initial injury, phenotypic changes follow a response to injury with release of endocrine and paracrine factors, primarily growth factors that provoke the deposition of extracellular matrix and the activation and proliferation of smooth muscle cells, pericytes and mesenchymal cells within the vessel wall. Vessel remodeling can occur with changes in cellular architecture and function [2, 3] (Fig. 2).
Fig. 2 Pf4+-macrophages are the major resource to generate second wave of pro-inflammatory factors at late stage of IAV-driven pneumonia. a Heat-maps showing the normalized expression (Z-score) of the pro-inflammatory genes in the various cells of clusters with high ratios at day 7 p.i.. b The normalized expression (UMI counts) of some significant genes with high expression in different clusters at day 7 p.i.. c Pf4+ cells in the lung after IAV infection. The tdtomato-Pf4 mice were uninfected or infected with 0.5 LD50 of influenza A/PR/8/34 (H1N1) viruses. At day 7 p.i, the tdtomato-Pf4+ cells in the lung were scanned. The nucleus was stained with DAPI (blue) and tomato-Pf4 (red) was shown in red. Scale bars, 500 μm. d At day 0 and day 7 p.i., the tdtomato-Pf4+ cells in the lung were calculated. At least 300 cells in each group from three independent assays were scored. Data are shown as the mean ± SD. **, P < 0.01 (Student t test, n = 3). e The expression of Ccl2 in Pf4+ cells. The tdTomato-Pf4 mice were infected with 0.5 LD50 of influenza A/PR/8/34 (H1N1) viruses. At day 7 p.i, the tdTomato-Pf4+ cells in the lung were stained with anti-Ccl2 antibodies (green). The nucleus was stained with DAPI (blue) and Pf4-tdTomato (red) was shown in red. Scale bars, left, 200 μm; right, 50 μm. f Heatmap showing the scaled distances calculated based on Pearson correlations for relationships between the z-score normalized mean expression profiles in all the indicated cells. g PCA plot showing the relationships among the indicated cell clusters and the megakarycytes from lung and bone mellow described by others (SRP097794, NCBI)
(From Zhang J. PLoS Pathol 2020;16: e1008334. With permission)