Smad1/5 is acetylated in the dorsal aortae of the mouse embryo before the onset of blood flow, driving early arterial gene expression.

AIMS: During embryonic development, arteriovenous (AV) differentiation ensures proper blood vessel formation and maturation. Defects in arterial or venous identity cause inappropriate fusion of vessels, resulting in atypical shunts, so-called arteriovenous malformations (AVM). Currently, the mechanism behind AVM formation remains unclear and treatment options are fairly limited. Mammalian AV differentiation is initiated before the onset of blood flow in the embryo; however, this pre-flow mechanism is poorly understood. Here, we aimed to unravel the role of Smad1/5 signalling in pre-flow arterial identity, and in the process uncovered an unexpected control mechanism of Smad1/5 signalling. METHODS AND RESULTS: We establish that despite Notch1 being expressed in the pre-flow mouse embryo, it is not activated, nor is it necessary for the expression of the earliest arterial genes in the dorsal aortae (i.e., Hey1 and Gja4). Furthermore, interrupting blood flow by using the Ncx1 KO model completely prevents the activation of Notch1 signalling, suggesting a strong role of shear stress in maintaining arterial identity. We demonstrate that early expression of Hey1 and Gja4 requires SMAD1/5 signalling. Using embryo cultures, we show that Smad1/5 signalling is activated through the Alk1/Alk5/TGFßR2 receptor complex, with TGFß1 as a necessary ligand. Furthermore, our findings demonstrate that early arterial gene expression requires the acetylation of Smad1/5 proteins, rendering them more sensitive to TGFß1 stimulation. Blocking acetyl-CoA production prevents pre-flow arterial expression of Hey1 and Gja4, while stabilizing acetylation rescues their expression. CONCLUSIONS: Our findings highlight the importance of the acetyl-CoA production in the cell and provide a novel control mechanism of Smad1/5 signalling involving protein acetylation. As disturbed canonical Smad1/5 signalling is involved in several vascular conditions, our results offer new insights in treatment options for circumventing canonical Smad1/5 signalling.

SARS-CoV-2 infection causes prolonged cardiomyocyte swelling and inhibition of HIF1α translocation in an animal model COVID-19.

Recovered COVID-19 patients often display cardiac dysfunction, even after a mild infection. Most current histological results come from patients that are hospitalized and therefore represent more severe outcomes than most COVID-19 patients face. To overcome this limitation, we investigated the cardiac effects of SARS-CoV-2 infection in a hamster model. SARS-CoV-2 infected hamsters developed diastolic dysfunction after recovering from COVID-19. Histologically, increased cardiomyocyte size was present at the peak of viral load and remained at all time points investigated. As this increase is too rapid for hypertrophic remodeling, we found instead that the heart was oedemic. Moreover, cardiomyocyte swelling is associated with the presence of ischemia. Fibrin-rich microthrombi and pericyte loss were observed at the peak of viral load, resulting in increased HIF1α in cardiomyocytes. Surprisingly, SARS-CoV-2 infection inhibited the translocation of HIF1α to the nucleus both in hamster hearts, in cultured cardiomyocytes, as well as in an epithelial cell line. We propose that the observed diastolic dysfunction is the consequence of cardiac oedema, downstream of microvascular cardiac ischemia. Additionally, our data suggest that inhibition of HIF1α translocation could contribute to an exaggerated response upon SARS-CoV-2 infection.

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity.

Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture.

Fluid flow as a driver of embryonic morphogenesis.

Fluid flow is a powerful morphogenic force during embryonic development. The physical forces created by flowing fluids can either create morphogen gradients or be translated by mechanosensitive cells into biological changes in gene expression. In this Primer, we describe how fluid flow is created in different systems and highlight the important mechanosensitive signalling pathways involved for sensing and transducing flow during embryogenesis. Specifically, we describe how fluid flow helps establish left-right asymmetry in the early embryo and discuss the role of flow of blood, lymph and cerebrospinal fluid in sculpting the embryonic cardiovascular and nervous system.