PDE5 Inhibition Stimulates Tie2-Expressing Monocytes and Angiopoietin-1 Restoring Angiogenic Homeostasis in Diabetes

Venneri, Mary Anna; Barbagallo, Federica; Fiore, Daniela; Gaetano, Rita De; Giannetta, Elisa; Sbardella, Emilia; Pozza, Carlotta; Campolo, Federica; Naro, Fabio; Lenzi, Andrea; Isidori, Andrea M.

doi:10.1210/jc.2018-02525

Cited by 22 publications

(19 citation statements)

References 52 publications

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“…These findings were then confirm in T2DM patients where 3 months of oral sildenafil (100 mg/day) reduced the endothelial function marker P‐selectin 49 . In pre‐clinical, as well as in clinical studies using chronic PDE5i with sildenafil 100 mg daily, we and others have shown that the NO‐cGMP‐PDE5 pathway and related targets are involved in the pathogenesis of several complications of diabetes affecting the immune system, 46‐48 adipose tissue, 50,51 and renal function 39 . A dose of 50mg of Sildenafil, given twice a week, was shown to improve surrogate markers of endothelial function (C‐reactive protein, endothelin‐1 and ICAM‐1, ANG‐1/TIE2 axis), modulating the number of circulating proangiogenic cells and exerting an anti‐inflammatory response in T2Dm patients 52 …”

Section: Introductionsupporting

confidence: 64%

“…[46][47][48] These findings were then confirm in T2DM patients where 3 months of oral sildenafil (100 mg/day) reduced the endothelial function marker P-selectin. 49 In pre-clinical, as well as in clinical studies using chronic PDE5i with sildenafil 100 mg daily, we and others have shown that the NO-cGMP-PDE5 pathway and related targets are involved in the pathogenesis of several complications of diabetes affecting the immune system, [46][47][48] adipose tissue, 50,51 and renal function. Its expression in men 53 is even higher, making them more responsive to PDE5i, as revealed in pulmonary hypertension (PH) and fibrosis.…”

Section: Introductionmentioning

confidence: 52%

“…In mouse models of diabetes, sildenafil restores normal levels of circulating TIE2‐expressing monocytes (TEMs), limiting inflammation, and promoting tissue repair 46‐48 . These findings were then confirm in T2DM patients where 3 months of oral sildenafil (100 mg/day) reduced the endothelial function marker P‐selectin 49 .…”

Section: Introductionmentioning

confidence: 76%

“…Chronic (6 months) PDE5 inhibition through vardenafil 10 mg/die has been shown to preserve endothelial function in T2DM patients, 45 probably due to an increase in angiogenic mediators, including Ang1 46 . These effects seem particularly important given that neutrophils isolated from patients with T2DM release larger amounts of proinflammatory cytokines, above all TNF‐α and IL‐6, 47 main players of the cytokine storm seen in COVID‐19 infection.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

et al. 2020

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Background A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm,” that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Objectives Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease. Materials and methods We performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial).” Results The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. Discussion and Conclusion If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.

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Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

et al. 2020

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“…The rise in Ang-2 may contribute to destabilize the vasculature, leading to uncontrolled neovascularization, as occurs in the late stage of diabetic retinopathy, or defective angiogenesis, thus impairing wound healing [29]. On the contrary, lower levels of Ang-1 have been found in patients with diabetes [35]. Therefore, the increased Ang-2/Ang-1 ratio may contribute to negatively affect Ang-1-Tie-2 signaling.…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End-Products and Hyperglycemia Increase Angiopoietin-2 Production by Impairing Angiopoietin-1-Tie-2 System

Puddu

Sanguineti

Maggi

et al. 2019

Journal of Diabetes Research

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The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1. We found that culture for 5 days in the presence of AGEs and HG (alone or in combination) decreased cell proliferation, increased reactive oxygen species (ROS) production, and reduced ratio between the oxidized and the reduced form of glutathione. Since angiopoietin-1 (Ang-1) signaling regulates angiopoietin-2 (Ang-2) expression through inactivation of the forkhead transcription factor FoxO1, we investigated intracellular signaling of Ang-1 and expression of Ang-2. HG and AGEs reduced phosphorylation of Akt and abrogated phosphorylation of FoxO1 induced by Ang-1 without affecting neither Tie-2 expression nor its activation. Furthermore, AGEs and/or HG induced nuclear translocation of FoxO1 and increased Ang-2 production. In conclusion, we demonstrated that both hyperglycemia and AGEs affect the angiopoietin-Tie-2 system by impairing Ang-1/Tie-2 signaling and by increasing Ang-2 expression. These results suggest that therapeutic strategies useful in preventing or delaying the onset of diabetic vascular complications should be aimed to preserve Ang-1 signaling.

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