Intussusceptive angiogenesis in Covid-19: hypothesis on the significance and focus on the possible role of FGF2

Abstract

The interest on the role of angiogenesis in the pathogenesis and progression of human interstitial lung diseases is growing, with conventional sprouting (SA) and non-sprouting intussusceptive angiogenesis (IA) being differently represented in specific pulmonary injury patterns. The role of viruses as key regulators of angiogenesis is known for several years. A significantly enhanced amount of new vessel growth, through a mechanism of IA, has been reported in lungs of patients who died from Covid-19; among the angiogenesis-related genes, fibroblast growth factor 2 (FGF2) was found to be upregulated. These findings are intriguing. FGF2 plays a role in some viral infections: the upregulation is involved in the MERS-CoV-induced strong apoptotic response crucial for its highly lytic replication cycle in lung cells, whereas FGF2 is protective against the acute lung injury induced by H1N1 influenza virus, improving the lung wet-to-dry weight ratio. FGF2 plays a role also in regulating IA, acting on pericytes (crucial for the formation of intraluminal pillars), and endothelium, and FGF2-induced angiogenesis may be promoted by inflammation and hypoxia. IA is a faster and probably more efficient process than SA, able to modulate vascular remodeling through pruning of redundant or inefficient blood vessels. We can speculate that IA might have the function of restoring a functional vascular plexus consequently to extensive endothelialitis and alveolar capillary micro-thrombosis observed in Covid-19. Anti-Vascular endothelial growth factor (anti-VEGF) strategies are currently investigated for treatment of severe and critically ill Covid-19 patients, but also FGF2, and its expression and/or signaling, might represent a promising target.

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study

“… 30 36 39 40 41 The cause of elevated thrombosis risk remains unclear, although proposed mechanisms have included systemic inflammation, endothelialitis, and activation of the complement system. 42 43 44 Increases in a variety of inflammatory pathways, including bradykinin, interleukin 6, C reactive protein, and growth differentiation factor 15, have been described in covid-19. 10 11 45 46 47 48 49 50 51 52 53 54 Further, heparin has been shown to block the SARS-CoV-2 viral spike protein from binding in experimental studies.…”

Iloprost in COVID-19: The Rationale of Therapeutic Benefit

“…Neutrophils and monocytes/macrophages actively participate in thrombosis and hemostasis cascade, but their role has not yet been sufficiently explored in COVID-19 infection. In COVID-19 pneumonia, persistent activation of circulating neutrophils and monocytes/macrophages, induced by the release of cytokines, in addition to IL-6, has been recently hypothesized (11). Previous observations documented that inflammation mediated by phagocytes in rat lungs is blocked by preincubation with anti-Mo1 monoclonal antibodies (heterodimeric glycoproteins expressed on the plasma membrane of neutrophils, monocytes, macrophages, and a subset of large granular lymphoid cells) preventing pulmonary injury.…”

“…Previous reports supposed that virus such as HIV and SARS-CoV2 can induce variations of serum levels of biomarkers of endothelial damage such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and Eselectin (9). It is also well-known that in COVID-19 infection, serum levels of fractalkine, VCAM-1, ICAM-1, and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase in correlation with disease course (10)(11)(12).…”

Nanotechnology to the Rescue: Treatment Perspective for the Immune Dysregulation Observed in COVID-19

“…In a study on rhesus macaques infected with SARS-CoV-2, the old macaques exhibited downregulation of genes associated with VEGF signaling unlike the juvenile macaques; which is remarkable, considering that elderly COVID-19 patients have increased levels of VEGF. In another study in rodents infected with SARS-CoV-2, it was found that the spike protein subverts VEGF-A/NRP-1 pro-nociceptive signaling causing amelioration of VEGF-A mediated pain (Chernyak et al, 2020;Colantuoni et al, 2020;Jin et al, 2020;Meini et al, 2020;Moutal et al, 2020;Perico et al, 2020;Rosa et al, 2020;Teuwen et al, 2020;Turkia, 2020;Pang et al, 2021).…”