Furthermore, Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Taken together, angiotensin II can promote vasoconstriction, inflammation, thrombosis, and vascular remodeling.

ANG II overexpression is a complete textbook description of the “cytokine storm” and hyperactive immune response seen in COVID-19. In the context of an inflammatory process, local activation of RAS and Ang II synthesis both increased vascular permeability by promoting the expression and secretion of VEGF (vascular endothelial growth factor) (Chua et al, 1998; Kitayama et al, 2006; Suzuki et al, 2003), and induced the expression of endothelial adhesive molecules including selectins (P- and L-selectin), vascular cell adhesion molecules-1 (VCAM-1), intercellular adhesion molecules-1 (ICAM-1) and their ligands, the integrins (Alvarez et al, 2004; Piqueras et al, 2000; Pueyo et al, 2000). Ang II also promotes endothelial dysfunction through COX-2 activation, which generates vasoactive prostaglandins and ROS (Welch, 2008; Wu et al, 2005). Moreover, Ang II favours the recruitment of infiltrating inflammatory cells into tissues by stimulating the production of specific cytokine/chemokines. For example, Ang II induces the production of the potent monocyte chemoattractant MCP-1 in cultured monocytes (Dai et al, 2007). In the aorta of spontaneously hypertensive rats, which bear elevated levels of Ang II, massive macrophage infiltration is accompanied by increased expression of MCP-1 and one of its receptors, the C–C chemokine receptor CCR2. Modulation of MCP-1/CCR2 via AT1 receptor blockade reduces vessel inflammation in these rats (Dai et al, 2007).