The article discusses the role of endothelial cells (ECs) in the pathogenesis of severe COVID-19. Emerging evidence suggests that ECs are essential contributors to the initiation and progression of severe disease. The study highlights that ECs contribute to acute respiratory distress syndrome (ARDS) by altering vessel barrier integrity, promoting a pro-coagulative state, inducing vascular inflammation (endotheliitis), and mediating inflammatory cell infiltration. During homeostasis, ECs maintain vascular integrity and prevent inflammation by limiting interactions with immune cells and platelets, and by expressing coagulation inhibitors and producing a glycocalyx with anti-coagulation properties. Recent studies using single-cell transcriptomics reveal that lung ECs exhibit immunomodulatory transcriptomic signatures, suggesting a role in immune surveillance against respiratory pathogens. However, ECs do not express CD80/CD86 co-activators, so they function as semi-professional antigen-presenting cells. After viral infection, severe disease develops in about 30% of hospitalized patients due to an over-reacting inflammatory response. Mechanistically, pulmonary complications result from vascular barrier breach, leading to tissue oedema, endotheliitis, activation of coagulation pathways, and deregulated inflammatory cell infiltration. The virus can directly affect ECs, and SARS-CoV-2 binding to ACE2 impairs its activity, increasing vascular permeability. Activated neutrophils and immune cells lead to enhanced EC contractility and inter-endothelial junction loosening, resulting in vascular leakage. Cytokines like IL-1β and TNF activate glucuronidases that degrade the glycocalyx, promoting fluid retention. Severe COVID-19 is associated with coagulation pathway activation and potential disseminated intravascular coagulation (DIC). ECs activated by IL-1β and TNF initiate coagulation by expressing P-selectin, von Willebrand factor, and fibrinogen. Platelets release VEGF, which triggers ECs to upregulate tissue factor, the prime activator of the coagulation cascade. This leads to lung tissue ischaemia, triggering angiogenesis and potential EC hyperplasia. The article also discusses the cytokine storm in severe cases, which amplifies EC dysfunction, DIC, inflammation, and vasodilation. EC dysfunction and activation likely co-determine this uncontrolled immune response. The role of ECs in the cytokine storm and potential therapeutic targets like S1PR1 are discussed. Additionally, the link between ECs, pericytes, and COVID-19 is explored, including risk factors for the disease and the possibility of ECs being gatekeepers of the immune response. The article concludes with the potential of vascular normalization strategies as therapeutic approaches in COVID-19.The article discusses the role of endothelial cells (ECs) in the pathogenesis of severe COVID-19. Emerging evidence suggests that ECs are essential contributors to the initiation and progression of severe disease. The study highlights that ECs contribute to acute respiratory distress syndrome (ARDS) by altering vessel barrier integrity, promoting a pro-coagulative state, inducing vascular inflammation (endotheliitis), and mediating inflammatory cell infiltration. During homeostasis, ECs maintain vascular integrity and prevent inflammation by limiting interactions with immune cells and platelets, and by expressing coagulation inhibitors and producing a glycocalyx with anti-coagulation properties. Recent studies using single-cell transcriptomics reveal that lung ECs exhibit immunomodulatory transcriptomic signatures, suggesting a role in immune surveillance against respiratory pathogens. However, ECs do not express CD80/CD86 co-activators, so they function as semi-professional antigen-presenting cells. After viral infection, severe disease develops in about 30% of hospitalized patients due to an over-reacting inflammatory response. Mechanistically, pulmonary complications result from vascular barrier breach, leading to tissue oedema, endotheliitis, activation of coagulation pathways, and deregulated inflammatory cell infiltration. The virus can directly affect ECs, and SARS-CoV-2 binding to ACE2 impairs its activity, increasing vascular permeability. Activated neutrophils and immune cells lead to enhanced EC contractility and inter-endothelial junction loosening, resulting in vascular leakage. Cytokines like IL-1β and TNF activate glucuronidases that degrade the glycocalyx, promoting fluid retention. Severe COVID-19 is associated with coagulation pathway activation and potential disseminated intravascular coagulation (DIC). ECs activated by IL-1β and TNF initiate coagulation by expressing P-selectin, von Willebrand factor, and fibrinogen. Platelets release VEGF, which triggers ECs to upregulate tissue factor, the prime activator of the coagulation cascade. This leads to lung tissue ischaemia, triggering angiogenesis and potential EC hyperplasia. The article also discusses the cytokine storm in severe cases, which amplifies EC dysfunction, DIC, inflammation, and vasodilation. EC dysfunction and activation likely co-determine this uncontrolled immune response. The role of ECs in the cytokine storm and potential therapeutic targets like S1PR1 are discussed. Additionally, the link between ECs, pericytes, and COVID-19 is explored, including risk factors for the disease and the possibility of ECs being gatekeepers of the immune response. The article concludes with the potential of vascular normalization strategies as therapeutic approaches in COVID-19.