endothelin-1 and Vitreoretinopathy--Proliferative

The pathology of the fibrotic proliferative vitreoretinopathy (PVR) membrane represents an excessive wound healing response characterised by cells' proliferation, migration and secretion of extracellular matrix molecules (ECMs). Retinal pigment epithelial (RPE) cells are a major cellular component of the fibrotic membrane. Endothelin-1 (ET-1) has been reported to be involved in the development of PVR in vivo research. However, little is known about the role of ET-1 in RPE cells in vitro. In the present study, we investigated the role of ET-1 in the proliferation, migration and secretion of ECMs (such as type I collagen and fibronectin) in RPE cells in vitro. Our results illustrated that ET-1 promoted the proliferation, migration and secretion of ECMs through the protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) signaling pathways in RPE cells in vitro. These findings strongly suggested that ET-1 may play a vital role in the development of PVR.

Topics: Cell Line; Cell Movement; Cell Proliferation; Collagen Type I; Cytokines; Endothelin-1; Extracellular Matrix; Fibronectins; Gene Expression Regulation; Humans; MAP Kinase Signaling System; Retinal Pigment Epithelium; Vitreoretinopathy, Proliferative

Ocular ischemic microenvironment plays a critical role in the progression of diabetic retinopathy (DR). In this study, we investigated the effect of vitreous and aqueous obtained from proliferative DR patients on the function of CD34⁺ cells derived from healthy humans. Human CD34⁺ cells were incubated with vitreous or aqueous of subjects with PDR. After incubation, cell migration of CD34⁺ was evaluated with CXCL12. Intracellular levels of nitric oxide (NO) were measured with DAF-FM. Tube formation assay was used to evaluate the effect of treated CD34⁺ cells on in vitro angiogenesis. Angiogenic protein array and mass spectrometry (MS) were performed to ascertain the factors secreted by healthy nondiabetic CD34⁺ cells exposed to diabetic vitreous or aqueous. PDR vitreous/aqueous reduced migration of CD34⁺ cells (672.45 ± 42.1/736.75 ± 101.7 AFU; P < 0.01) and attenuated intracellular NO levels (182 ± 1.4/184.5 ± 6.3 AFU, P = 0.002). Pretreatment with PDR vitreous suppressed tube formation of human retinal endothelial cells (64 ± 1.6 vs. 80 ± 2.5). CD34⁺ exposed to PDR vitreous resulted in the increased expression of CXCL4 and serpin F1, whereas CD34⁺ exposed to PDR aqueous showed increased expression of CXCL4, serpin F1, and endothelin-1 (ET-1). MS analysis of CD34⁺ (exposed to PDR vitreous) expressed J56 gene segment, isoform 2 of SPARC-related modular calcium-binding protein 2, isoform 1 of uncharacterized protein c1 orf167, integrin α-M, and 40s ribosomal protein s21. Exposure of healthy nondiabetic CD34⁺ cells to PDR vitreous and aqueous resulted in decreased migration, reduced generation of NO, and altered paracrine secretory function. Our results suggest that the contribution of CD34⁺ cells to the aberrant neovascularization observed in PDR is driven more by the proangiogenic effects of the retinal cells rather than the influence of the vitreous.

Topics: Adult; Adult Stem Cells; Aged; Antigens, CD34; Aqueous Humor; Bone Marrow Cells; Cells, Cultured; Chemotaxis; Diabetic Retinopathy; Endothelin-1; Eye Proteins; Humans; Middle Aged; Neovascularization, Pathologic; Nerve Growth Factors; Nitric Oxide; Peptide Mapping; Platelet Factor 4; Retina; Serpins; Vitreoretinopathy, Proliferative; Vitreous Body

To analyze if endothelin 1 may have an effect on central retinal artery (CRA) blood flow velocities and intraocular pressure (IOP) in retinal detachment.. Using radioimmunoassay, immunoreactive endothelin 1 levels were tested in both plasma and subretinal fluid specimens from patients with retinal detachment, while only plasma specimens from healthy subjects were tested. Central retinal artery Doppler sonography parameters and IOP were measured in eyes with retinal detachment, with and without proliferative vitreoretinopathy, their respective healthy fellow eyes, and normal eyes.. Retinal detachment eyes had lower CRA peak systolic velocity and end-diastolic velocity, lower IOP, and higher plasma immunoreactive endothelin 1 levels than normal eyes (P < 0.0001). Eyes with proliferative vitreoretinopathy had lower CRA peak systolic velocity and end-diastolic velocity, higher resistivity index, lower IOP, higher plasma immunoreactive endothelin 1 levels, and higher subretinal fluid immunoreactive endothelin 1 than eyes without proliferative vitreoretinopathy (P < 0.0001). A statistically significant linear correlation was found among CRA parameters, IOP, and subretinal fluid immunoreactive endothelin 1 measurements.. Endothelin 1 has shown a close relationship with IOP and CRA blood flow changes associated to retinal detachment as well as with proliferative vitreoretinopathy complications.

Topics: Adult; Aged; Blood Flow Velocity; Blood Pressure; Cross-Sectional Studies; Endothelin-1; Female; Humans; Intraocular Pressure; Male; Middle Aged; Prospective Studies; Radioimmunoassay; Retinal Artery; Retinal Detachment; Subretinal Fluid; Tonometry, Ocular; Ultrasonography, Doppler, Color; Vitreoretinopathy, Proliferative

To find models that will explain the variability in postoperative visual acuity (VA) (logarithmic: logMAR) associated with unilateral primary rhegmatogenous retinal detachment (RD).. This was a prospective clinical cohort study of 33 patients with proliferative vitreoretinopathy (PVR: PVR

Topics: Adult; Aged; Blood Flow Velocity; Blood Pressure; Endothelin-1; Female; Humans; Intraocular Pressure; Male; Middle Aged; Models, Statistical; Postoperative Period; Prospective Studies; Radioimmunoassay; Retinal Artery; Retinal Detachment; Scleral Buckling; Subretinal Fluid; Time Factors; Ultrasonography, Doppler; Visual Acuity; Vitreoretinopathy, Proliferative

To analyze whether preoperative duration of primary rhegmatogenous retinal detachment (RD) influences endothelin-1 (ET-1)--a vasoactive, mitogenic, and pro-apoptotic peptide- levels with repercussions on logarithmic (LogMAR) visual acuity (VA).. Prospective clinical cohort study on 66 healthy patients [33 with proliferative vitreoretinopathy (PVR) and 33 with no PVR] with unilateral RD candidates for scleral buckling (SB) surgery. Using radioimmunoassay, immunoreactive ET-1 (IR-ET-1) was tested in both plasma and subretinal fluid (SRF) of these RD patients. Pearson's correlations were evaluated between preoperative RD duration and each IR-ET-1 level (plasma, SRF and the difference SRF minus plasma) and also between both variables and the LogMAR VAs (preoperative, postoperative 8 months, and the difference: postoperative 8 months minus preoperative).. PVR was associated with higher preoperative RD duration, higher LogMAR VA values (pre- and postoperative 8 months) and higher IR-ET-1 values (plasma, SRF and the difference: SRF minus plasma) than no-PVR IR-ET-1 levels (plasma and SRF) were only correlated (r = 0.462, p = 0.007; r = 0.397, p = 0.022 respectively) with preoperative RD duration in the no-PVR group. IR-ET-1 values (plasma, SRF and the difference:SRF minus plasma) showed statistically significant correlations with pre- and with postoperative 8 months LogMAR VAs in no-PVR and with postoperative 8 months LogMAR VA and LogMAR VA difference in PVR The highest correlation between IR-ET-1 levels and LogMAR VAs was found between SRF IR-ET-1 and postoperative 8 months LogMAR VA in PVR (cases with macula-on) (r = 0.956, p < 0.0001).. Preoperative RD duration showed statistically significant positive correlations with pre- and with postoperative 8 months LogMAR VAs in both the no-PVR and the PVR groups and with IR-ET-1 measurements (plasma and SRF: lower correlations) only in the no-PVR group. These findings support the idea of doing primary and prompt vitrectomy for RD and perhaps using coadjutant pharmacologic therapy in order to improve visual results.

Topics: Adult; Aged; Body Fluids; Endothelin-1; Female; Humans; Intraocular Pressure; Male; Middle Aged; Prospective Studies; Radioimmunoassay; Recurrence; Retinal Detachment; Scleral Buckling; Time Factors; Visual Acuity; Vitreoretinopathy, Proliferative

To analyze if endothelin-1 (ET-1) may have an effect on ophthalmic artery (OA) blood flow velocities and intraocular pressure (IOP) in retinal detachment (RD).. Using radioimmunoassay, immunoreactive (IR) ET-1 levels were tested in both plasma and subretinal fluid (SRF) specimens from patients with RD, while only plasma specimens from normal (healthy) subjects were tested. OA Doppler sonography parameters and IOP were measured in eyes with RD, with and without proliferative vitreoretinopathy (PVR), their respective healthy fellow eyes, and normal eyes.. RD eyes had lower OA peak systolic velocity (PSV) and end diastolic velocity (EDV), higher resistivity index (RI), lower IOP, and higher plasma IR ET-1 levels than normal eyes (P < 0.0001). Eyes with PVR had lower OA PSV and EDV, higher RI, lower IOP, higher plasma IR ET-1 levels, and higher SRF IR ET-1 than eyes without PVR (P < 0.0001). A statistically significant linear correlation was found among OA parameters, IOP, and SRF IR ET-1 measurements.. Decreased OA blood flow velocities may explain lower IOP found in RD patients, and ET-1 levels may be responsible for both measurements.

Topics: Adult; Aged; Blood Flow Velocity; Blood Pressure; Cross-Sectional Studies; Endothelin-1; Exudates and Transudates; Female; Humans; Intraocular Pressure; Male; Middle Aged; Ophthalmic Artery; Prospective Studies; Radioimmunoassay; Regional Blood Flow; Retinal Detachment; Tonometry, Ocular; Ultrasonography, Doppler, Color; Vitreoretinopathy, Proliferative

Proliferative vitreoretinopathy (PVR) is characterized by severe glial remodeling. Glial activation and proliferation that occur in brain diseases are modulated by endothelin-1 (ET-1) and its receptor B (ETR-B). Because retinal astrocytes contain ET-1 and express ETR-B, we studied the changes of these molecules in an experimental mouse model of PVR and in human PVR. Both ET-1 and ETR-B immunoreactivities increased in mouse retina after induction of PVR with dispase. Epi- and subretinal outgrowths also displayed these immunoreactivities in both human and experimental PVR. Additionally, myofibroblasts and other membranous cell types showed both ET-1 and ETR-B immunoreactivities. In early stages of experimentally induced PVR, prepro-ET-1 and ETR-B mRNA levels increased in the retina. These mRNA levels also increased after retinal detachment (RD) produced by subretinal injection. Treatment of mice with tezosentan, an antagonist of endothelinergic receptors, reduced the histopathological hallmarks of dispase-induced PVR: retinal folding, epiretinal outgrowth, and gliosis. Our findings in human and in dispase-induced PVR support the involvement of endothelinergic pathways in retinal glial activation and the phenotypic transformations that underlie the growth of membranes in this pathology. Elucidating these pathways further will help to develop pharmacological treatments to prevent PVR. In addition, the presence of ET-1 and ETR-B in human fibrous membranes suggests that similar treatments could be helpful after PVR has been established.

Topics: Animals; Endopeptidases; Endothelin B Receptor Antagonists; Endothelin-1; Fluorescent Antibody Technique; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Injections; Mice; Mice, Inbred C57BL; Pyridines; Receptor, Endothelin B; Retina; Retinal Detachment; RNA, Messenger; Tetrazoles; Vitreoretinopathy, Proliferative

To analyze whether subretinal (SRF) endothelin-1 (ET-1) - a vasoactive, mitogenic, and pro-apoptotic peptide - levels are related to visual acuity (VA) in rhegmatogenous retinal detachment (RD).. Sixty-six healthy patients between 42 and 70 years of age with unilateral RD, all candidates for scleral buckling surgery (PVR

Topics: Adult; Aged; Endothelin-1; Female; Humans; Male; Middle Aged; Retina; Retinal Detachment; Scleral Buckling; Visual Acuity; Vitreoretinopathy, Proliferative

Endothelin one (ET-1) is a vasomodulator peptide that plays a role on ocular blood flow, glial proliferation, and collagen matrix contraction by retinal pigmented epithelial (RPE) cells. Both glial and RPE cells have been involved in the formation of epiretinal membranes (ERMs). This investigation was conducted to determine whether ET-1 may be associated with ERMs, either idiopathic (IERMs) or from proliferative vitreoretinopathy (PVR).. Plasma and vitreous samples were collected from patients classified by the presence of PVR membranes, retinal detachment (RD), and other ocular conditions, such as IERMs, that made the patients candidates for vitrectomy. Immunoreactive endothelin one (IR-ET-1) was tested in plasma and vitreous by radioimmunoassay. Immunoreactive-ET-1 was localized in IERMs and PVR membranes immunohistochemically. Expression of endothelin receptors A (ETA) and B (ETB) was confirmed by reverse transcription-polymerase chain reaction.. IR-ET-1 levels in plasma and vitreous were higher in patients with PVR and in patients with RD than in those of the control group. Eyes with IERMs also showed higher IR-ET-1 levels than the control group cases. IR-ET-1 levels in eyes with PVR were higher than those in eyes with IERMs. IR-ET-1 levels in eyes with RD were also higher than those of eyes with IERMs. Immunoreactive ET-1 was localized in the cellular and stromal components of both IERMs and PVR membranes. Furthermore, ETA and ETB receptors were expressed in both IERMs and PVR membranes.. IR-ET-1 in human vitreous is elevated in PVR, RD, and IERMs. ET-1 and its receptors ETA and ETB are present in epiretinal tissue of both idiopathic and PVR membranes. These data suggest an involvement of ET-1 in retinal disease.

Topics: Adult; Aged; Aged, 80 and over; Endothelin-1; Epiretinal Membrane; Female; Glial Fibrillary Acidic Protein; Humans; Keratins; Male; Middle Aged; Radioimmunoassay; Receptor, Endothelin A; Receptor, Endothelin B; Retinal Detachment; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vitreoretinopathy, Proliferative; Vitreous Body