The misunderstood link between SARS-CoV-2 and angiogenesis. A narrative review.

Novel Coronavirus Disease 2019 (Covid-19) is associated with multi-systemic derangement, including circulatory dysfunction with features of endothelial dysfunction, microangiopathic thrombosis and angiocentric inflammation. Recently, intussusceptive angiogenesis has been implicated in the pathogenesis of the disease. Herein, we conducted a narrative review according to the SANRA guidelines to review and discuss data regarding splitting angiogenesis including mechanisms, drivers, regulators and putative roles. Relevant angiogenic features in Covid-19, including their potential role in inflammation, endothelial dysfunction and permeability, as well as their use as prognostic markers and therapeutic roles are reviewed. Splitting angiogenesis in Covid-19 involve hypoxia, hypoxia-inducible factors, classic angiogenic mediators, such as the Vascular Endothelial Growth Factor (VEGF), Angiopoietins, hyperinflammation and cytokine storm, and dysregulation of the Renin-Angiotensin-Aldosterone System, which combined, interact to promote intussusception. Data regarding the use of angiogenic mediators as prognostic tools is summarized and suggest that angiopoietins and VEGF are elevated in Covid-19 patients and predictors of adverse outcomes. Finally, we reviewed the scarce data regarding angiogenic mediators as therapeutic targets. These preliminary findings suggest a potential benefit of bevacizumab as an add-on therapy.