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English: Pathogenic mechanisms in vascular endothelium during initial orthohantavirus infection. (A) Healthy vascular ECs contain a tightly regulated barrier, mainly based on adherens junction molecules such as VE-cadherin. (B) Important soluble factors that maintain this barrier function are bradykinin and VEGF. As response to infection, ECs produce and secrete VEGF. (C) Local VEGF binds to endothelial receptors and disengages adherens junctions by increased nitric oxide production and internalization of VE-cadherin. (D) Under hypoxic conditions (for instance due to pulmonary edema), these effects are even expanded as VEGF production is increased, causing increased vascular permeability. (E) In addition, orthohantavirus particles present on the endothelial cell surface recruit quiescent platelets to endothelial cell surfaces. This increased consumption of blood platelets may contribute in part to thrombocytopenia. Both the permeabilizing effects of secreted VEGF and the recruitment of platelets lead to internalization of VE-cadherin (i.e., loss of endothelial barrier function).