Vitreous protein networks around ANG2 and VEGF in proliferative diabetic retinopathy and the differential effects of aflibercept versus bevacizumab pre-treatment

Klaassen, Ingeborg; Avery, Peter; Schlingemann, Reinier O.; Steel, David

doi:10.1038/s41598-022-25216-z

Cited by 4 publications

(2 citation statements)

References 64 publications

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“…Eyes with active PDR exhibited higher Ang2 levels than inactive PDR. Furthermore, the levels of Ang2 correlated with those of VEGF [170]. Another cross sectional study reported that in eyes with PDR, Ang1, Ang2, VEGF-A, PlGF, Il-8 and Il1b were all elevated when compared to non-diabetic eyes [171].…”

Section: Diabetic Patients and Ang-tie Signalingmentioning

confidence: 89%

Beyond VEGF: Angiopoietin–Tie Signaling Pathway in Diabetic Retinopathy

Chen-Li,

Martinez-Archer,

Coghi

et al. 2024

JCM

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Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin–Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

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Section: Diabetic Patients and Ang-tie Signalingmentioning

confidence: 89%

Beyond VEGF: Angiopoietin–Tie Signaling Pathway in Diabetic Retinopathy

Chen-Li,

Martinez-Archer,

Coghi

et al. 2024

JCM

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“…Vascular endothelial growth factor A (VEGF-A), higher levels of which are present in the vitreous of patients with DR, DME, or RVO, elevates the permeability of the retinal endothelium, playing a key role in the pathophysiology of macular edema (3)(4)(5)(6)(7). Higher concentrations in the vitreous or aqueous humor of inflammatory cytokines, such as interleukin (IL)-6 and IL-1β are not only associated with the pathogenesis of RVO, respectively, but also with the development of DME and proliferative DR (8)(9)(10)(11)(12). Additionally, the ocular renin-angiotensin aldosterone-system (RAAS) also regulates the retinal blood and fluid balance; several studies point to its major role in the development of DME (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Different responses of the MIO‑M1 Mueller cell line to angiotensin II under hyperglycemic or hypoxic conditions

Beuse,

Deissler,

Hollborn

et al. 2023

Biomed Rep

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Members of the renin-angiotensin aldosterone system (RAAS) are expressed by various retinal tissues including Mueller glial cells. As the RAAS is hypothesized to play an important role in the pathogenesis of diseases that threaten vision, such as diabetic macular edema or retinal vein occlusion, the possible changes induced by exposure of the human cell line MIO-M1, an established model of Mueller cells, to angiotensin II or aldosterone for 6 h under hypoxic and/or hyperglycemic conditions were investigated. The mRNA expression levels of the members of the RAAS were assessed by reverse transcription-quantitative PCR, and the secretion of cytokines was assessed by ELISA. Under hyperglycemic conditions, the mRNA expression levels of the angiotensin-converting enzyme 2 (ACE2), angiotensin II receptors, AT 1 and AT 2, and the receptor of angiotensin (1-7) MAS1 were significantly higher after exposure to angiotensin II, and the expression of ACE2, AT 2 , and IL-6 (a marker of inflammation) was significantly increased after treatment with aldosterone; the expression of the other targets investigated remained unchanged. Significantly more IL-6 was secreted by MIO-M1 cells exposed to hyperglycemia and angiotensin. When cells were cultured in a hypoxic environment, additional treatment with aldosterone significantly increased the mRNA expression levels of ACE, but significantly more ACE2 mRNA was expressed in the presence of angiotensin II. Under hypoxic plus hyperglycemic conditions, significantly less ACE but more AT 2 was expressed after treatment with angiotensin II, which also led to strongly elevated expression of IL-6. The mRNA expression levels of the angiogenic growth factor VEGF-A and secretion of the encoded protein were notably increased under hypoxic and hypoxic plus hyperglycemic conditions, irrespective of additional treatment with angiotensin II or aldosterone. These findings suggest that angiotensin II induces a pro-inflammatory response in MIO-M1 cells under hyperglycemic conditions despite activation of the counteracting ACE2/MAS1 signaling cascade. However, hypoxia results in an increased expression of angiogenic VEGF-A by these cells, which is not altered by angiotensin II or aldosterone.

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