The role of sirt1 in the formation of retinal miroaneurysms during aging
- Autores: Joana Araújo Nobre Catita
- Directores de la Tesis: Jesús Ruberte París (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Rafael Simó Canonge (presid.), Maria Luísa Mendes Jorge (secret.), Alan Williams (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina y Sanidad Animales por la Universidad Autónoma de Barcelona
- Materias:
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- Resumen
First discovered in 1888 by Nettleship, microaneurysms are described as saccular dilations that arise from capillaries. Since then, several theories have been suggested to explain the appearance of retinal microaneurysms, yet the exact mechanisms by which these focal dilatations develop are still uncertain. Retinal microaneurysms are frequently found in early stages of diabetic retinopathy, and less commonly in hypertension, retinal venous occlusion, as well as in aging. The manifestation of microaneurysms is considered an important sign in the progression of retinal diseases. Thus, understanding the process of microaneurysm formation is of significant interest, not only for preventing and/or limiting microaneurysms progression, but it may also prove useful for finding a more successful treatment of retinal diseases associated with microaneurysms.
The present study uncovers a new role for Sirt1 in the progression of retinal microaneurysms. Sirt1 is believed to play a protective function in several retinal vascular disorders. However our results revealed an unexpected overexpression of Sirt1 in the wall of human retinal microaneurysms during aging. In this regard, the aim of this study was to determine if Sirt1 is acting as a promoter of microaneurysm formation opposed to the putative protective effect described by other authors. For this purpose, we analyzed the function of Sirt1 in the retinal blood vessels of mice by means of gain- and loss-of-function experiments, where the effects of overexpressing SIRT1 in the retina were rigorously investigated, as well as its conditional deletion in endothelial cells.
To address the impact of SIRT1 upregulation we used SIRT1 transgenic (Sirt1-tg) mice which showed a moderate increase (~3-fold) in the expression of Sirt1 in the retina. This mouse model provided evidence that Sirt1 overexpression affected the retinal vasculature while preserving the structural integrity of the retina. The overexpression of Sirt1 induced a mild angiogenic phenotype in the retinal blood vessels concomitant with upregulation of VEGF and characterized by increased arteriolar tortuosity, “sausage-string” like appearance of arterioles, blood basement membrane thickening, as well as moderate vascular leakage of the retinal capillaries. Furthermore, PDGF-B/PDGFR-β signaling was increased during Sirt1 overexpression associated with enhanced expression of well-recognized pericyte markers NG2 and PDGFR-β, thus demonstrating that pericytes were recruited to the vascular wall. On the contrary, specific deletion of SIRT1 in endothelial cells did not impact the integrity of the retinal vasculature, as endothelial-restricted SIRT1 mutant mice showed a normal retinal vascular pattern without significant morphological and structural alterations.
These results lead us to speculate if the overexpression of Sirt1 observed in human microaneurysms might be regulated by identical signaling pathways observed in Sirt1-tg mice. Accordingly, we found that both VEGF and pericyte number are focally increased in human retinal microaneurysms during aging.
Taking into account these results, and previous studies reported by us and other authors, we hypothesized that once an initial microaneurysm is formed, either it progresses towards its repair (Vasoprotection) or it leads to the exacerbation of this lesion into a larger microaneurysm (Vasoregression). Vasoprotection mechanisms could be regulated by Sirt1 by means of VEGF-mediated response, which promotes endothelial cell survival and proliferation. In addition, the increased activation of PDGF-B/PDGFRβ signaling recruits pericytes to the microaneurysms, which in turn produces extracellular matrix in an effort to stabilize the capillary basement capillary. In contrast, Vasoregression mechanisms are triggered by apoptosis and cellular senescence, which lead respectively to pericyte and endothelial cell loss. The overexpression of matrix metalloproteinases, a characteristic feature of senescence associated secretory phenotype will produce weakening of the basement membrane. These shifting mechanisms of vasoprotection and vasoregression could determine the fate of retinal microaneurysms and may explain the turnover of microaneurysms found clinically in human retina.
