COVID-19 and dys-regulation of pulmonary endothelium: implications for vascular remodeling.

Coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome-coronavirus-2, has claimed more than 4.4 million lives worldwide (as of 20 August 2021). Severe cases of the disease often result in respiratory distress due to cytokine storm, and mechanical ventilation is required. Although, the lungs are the primary organs affected by the disease, more evidence on damage to the heart, kidney, and liver is emerging. A common link in these connections is the cardiovascular network. Inner lining of the blood vessels, called endothelium, is formed by a single layer of endothelial cells. Several clinical manifestations involving the endothelium have been reported, such as its activation via immunomodulation, endotheliitis, thrombosis, vasoconstriction, and distinct intussusceptive angiogenesis (IA), a unique and rapid process of blood-vessel formation by splitting a vessel into two lumens. In fact, the virus directly infects the endothelium via TMPRSS2 spike glycoprotein priming to facilitate ACE-2-mediated viral entry. Recent studies have indicated a significant increase in remodeling of the pulmonary vascular bed via intussusception in patients with COVID-19. However, the lack of circulatory biomarkers for IA limits its detection in COVID-19 pathogenesis. In this review, we describe the implications of angiogenesis in COVID-19, unique features of the pulmonary vascular bed and its remodeling, and a rapid and non-invasive assessment of IA to overcome the technical limitations in patients with COVID-19.

Inhibition of hypoxia-induced Mucin 1 alters the proteomic composition of human osteoblast-produced extracellular matrix, leading to reduced osteogenic and angiogenic potential.

The bone microenvironment is one of the most hypoxic regions of the human body and in experimental models; hypoxia inhibits osteogenic differentiation of mesenchymal stromal cells (MSCs). Our previous work revealed that Mucin 1 (MUC1) was dynamically expressed during osteogenic differentiation of human MSCs and upregulated by hypoxia. Upon stimulation, its C-terminus (MUC1-CT) is proteolytically cleaved, translocases to the nucleus, and binds to promoters of target genes. Therefore, we assessed the MUC1-mediated effect of hypoxia on the proteomic composition of human osteoblast-derived extracellular matrices (ECMs) and characterized their osteogenic and angiogenic potentials in the produced ECMs. We generated ECMs from osteogenically differentiated human MSC cultured in vitro under 20% or 2% oxygen with or without GO-201, a MUC1-CT inhibitor. Hypoxia upregulated MUC1, vascular endothelial growth factor, and connective tissue growth factor independent of MUC1 inhibition, whereas GO-201 stabilized hypoxia-inducible factor 1-alpha. Hypoxia and/or MUC1-CT inhibition reduced osteogenic differentiation of human MSC by AMP-activated protein kinase/mTORC1/S6K pathway and dampened their matrix mineralization. Hypoxia modulated ECMs by transforming growth factor-beta/Smad and phosphorylation of NFκB and upregulated COL1A1, COL5A1, and COL5A3. The ECMs of hypoxic osteoblasts reduced MSC proliferation and accelerated their osteogenic differentiation, whereas MUC1-CT-inhibited ECMs counteracted these effects. In addition, ECMs generated under MUC1-CT inhibition reduced the angiogenic potential independent of oxygen concentration. We claim here that MUC1 is critical for hypoxia-mediated changes during osteoblastogenesis, which not only alters the proteomic landscape of the ECM but thereby also modulates its osteogenic and angiogenic potentials.