The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver fibrosis as well as during atheromatous plaque formation. Special attention is paid to the specific features characterizing each of these processes, including the spectrum of different myofibroblast precursors and the distinct pathways involved in the formation of differentiated myofibroblasts in each lesion. Thus, whereas in lung fibrosis it seems that most myofibroblasts derive from resident fibroblasts, hepatic stellate cells are the main contributor for liver fibrosis and media smooth muscle cells are the main contributor for the atheromatous plaque. A better knowledge of the molecular mechanisms conducive to the appearance of differentiated myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and for the planning of strategies aiming at their prevention and therapy.

Transforming growth factor-β1 (TGFβ1), a major promoter of myofibroblast differentiation, induces α-smooth muscle (sn) actin, modulates the expression of adhesive receptors, and enhances the synthesis of extracellular matrix (ECM) molecules including ED-A fibronectin (FN), an isoform de novo expressed during wound healing and fibrotic changes. We report here that ED-A FN deposition precedes α-SM actin expression by fibroblasts during granulation tissue evolution in vivo and after TGFβ1 stimulation in vitro. Moreover, there is a correlation between in vitro expression of α-SM actin and ED-A FN in different fibroblastic populations. Seeding fibroblasts on ED-A FN does not elicit per se α-SM actin expression; however, incubation of fibroblasts with the anti-ED-A monoclonal antibody IST-9 specifically blocks the TGFβ1-triggered enhancement of α-SM actin and collagen type I, but not that of plasminogen activator inhibitor-1 mRNA. Interestingly, the same inhibiting action is exerted by the soluble recombinant domain ED-A, but neither of these inhibitory agents alter FN matrix assembly. Our findings indicate that ED-A–containing polymerized FN is necessary for the induction of the myofibroblastic phenotype by TGFβ1 and identify a hitherto unknown mechanism of cytokine-determined gene stimulation based on the generation of an ECM-derived permissive outside in signaling, under the control of the cytokine itself.

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.

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IntroductionFamilial macrothrombocytopenias with leukocyte inclusion bodies are a group of rare autosomal dominant disorders characterized by mild bleeding symptoms, giant platelets, and Döhle-like inclusion bodies in peripheral blood granulocytes. These disorders, which include the May-Hegglin anomaly (MHA; OMIM [Online Mendelian Inheritance in Man], #155100), Sebastian syndrome (SBS; OMIM, #605249), Fechtner syndrome (FTNS; OMIM, #153640), and Epstein syndrome (EPS; OMIM, #153650) all have largely overlapping phenotypes but were previously considered as separate clinical entities. [1][2][3][4] Biochemical analysis of platelets from patients with MHA revealed no abnormalities in the function of these cells, 5,6 leading to the hypothesis that the hematologic phenotype in patients may result from a deficit in the demarcation membranes in megakaryocytes prior to platelet formation. 7 MHA and SBS are distinguished from each other by small differences in their inclusion bodies revealed by electron microscopy examination. 8 FTNS and EPS, however, manifest a number of nonhematologic traits similar to those observed in Alport syndrome cases, such as nephritis, high-tone sensorineural deafness, and bilateral cataracts, all of which are present with variable expressivity. 1,9,10 The discovery that the genetic loci for all of these syndromes mapped to chromosome 22q12.3 Ϫq13.2, 11-13 and the identification of mutations in the MYH9 gene for each of them, showed that this group of pathologies represent allelic variations of a single genetic disorder. [14][15][16][17][18] MYH9, a 5.8-kb (kilobase) mRNA transcript, encodes for the nonmuscle myosin heavy chain A (also known as NMMHC-A), a large cytoplasmic protein that forms part of the myosin II hexameric complex. 19,20 MYH9 consists of an adenosine triphosphatase (ATPase) globular head domain at its N-terminus and a C-terminal tail domain that forms a coiled coil structure on dimerization.The function of nonmuscular myosin II (MYH9 containing) has not been fully characterized. 21 It has been shown to form clusters of minifilaments in the cytoplasm, which concentrate in stress fibers near the periphery of cells and in the cleavage furrow of dividing cells. 22 Nonmuscular myosin is involved in processes such as phagocytosis 23 and cytokinesis, and in the latter it is thought to drive constriction of the cleavage furrow, as shown elegantly in Dictyostelium discoideum, where myosin IInull cells fail to divide. 24 These data are consistent with the originally proposed disease mechanism of impaired thrombopoiesis as a result of defects in cytoskeleton rearrangement in megakaryocytes, 7 although this is still a poorly understood process.The MYH9 gene has subsequently been found to be involved in 2 further disorders, DFNA17 (OMIM, #603622), an autosomal 25 and APSM (OMIM, #153650), a variant of Alport syndrome with macrothrombocytopenia. 16 To date, 20 different disease-associated mutations have been found in the MYH9 gene, covering the range of phenotypes represented by the 6 clin...