The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels.
The roles of transforming growth factor (TGF)-β in extracellular matrix production and vascular remodeling, coupled with increased TGF-β expression and signaling in diabetes, suggest TGF-β as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-β signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-β receptor activin receptor-like kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-β signaling in retinal vessels of diabetic rats. At the level of vascular gene expression, 3.5 months' diabetes induced minimal changes. Diabetes + SM16 for 3 weeks caused widespread changes in gene expression poised to enhance vascular inflammation, thrombosis, leakage, and wall instability; these changes were not observed in control rats given SM16. The synergy of diabetes and SM16 in altering gene expression was not observed in the lung. At the level of vascular network morphology, 7 months' diabetes induced no detectable changes. Diabetes + SM16 for 3 weeks caused instead distorted morphology and decreased density. Thus, in diabetes, retinal vessels become dependent on a small increase in TGF-β signaling via activin receptor-like kinase 5 to maintain early integrity. The increased TGF-β signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions.
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Zeina
Z
Dagher
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Chiara
C
Gerhardinger
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts.
Joseph
J
Vaz
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts.
Michael
M
Goodridge
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Francesco
F
Tecilazich
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address: mara_lorenzi@meei.harvard.edu.
Mara
M
Lorenzi
D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006442:Glycated Hemoglobin / Q000378:metabolism; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D029404:Activin Receptors; D053961:Azabicyclo Compounds; D001786:Blood Glucose; D018932:Chemokine CCL2; D006442:Glycated Hemoglobin; D048308:Mitogen-Activated Protein Kinase 14; D016212:Transforming Growth Factor beta; C526764:Acvrl1 protein, rat; C528106:SM16 compound