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Luis Alarcon-Martinez, Jorge Luis Cueva Vargas, Nicolas A Belforte, Deborah villafranca-Baughman, Adriana Di Polo; Pericytes promote capillary constriction in ocular hypertension glaucoma that persists after lowering intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4474. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Pericytes are contractile cells that wrap along the walls of capillaries, regulating their diameter and vascular blood flow in response to metabolic demand. The contribution of pericytes to microvascular deficits in glaucoma is poorly understood. To address this, we used genetic tools in combination with live imaging and ex vivo analyses of pericytes in a mouse glaucoma model. Furthermore, we investigated the pericyte response before and after lowering intraocular pressure (IOP).
Ocular hypertension was induced by injection of magnetic microbeads into the anterior chamber of transgenic mice carrying the pericyte-specific NG2 promoter driving red fluorescent protein (NG2:DsRed) or the genetically encoded calcium indicator GCaMP6 (NG2:GCaMP6). Minimally invasive, multiphoton imaging of live mice was used to visualize pericytes, calcium dynamics, and capillary diameter after glaucoma induction. Ex vivo measurements of capillary diameter at pericyte locations were carried out using an unbiased stereological approach. The pericyte response was monitored before and after IOP reduction by daily topical instillation of timolol.
Live two-photon imaging and ex vivo analysis of NG2:DsRed retinas demonstrated that ocular hypertension induced a gradual and substantial decrease in capillary diameter at pericyte locations (sham controls: 4.7 ± 0.1 μm, glaucoma: 4.0 ± 0.1 μm, 3 weeks of high IOP, n=5-6 mice/group, Student’s t-test p<0.05). Analysis of NG2:GCaMP6 retinas showed that pericyte contraction correlated tightly with intracellular calcium accumulation in pericytes. Intriguingly, in spite of successful IOP lowering (vehicle: 18.6 ± 0.7 mm Hg, timolol: 15.0 ± 0.4 mm Hg, n=5-7 mice/group) pericytes remained contracted leading to a sustained decrease in capillary diameter (naïve controls: 4.7 ± 0.1 μm, glaucoma + vehicle: 4.0 ± 0.1 μm, glaucoma + timolol: 3.4 ± 0.1 μm, timolol: 4.0 ± 0.1 μm, n=5-7 mice/group, ANOVA, Tukey’s test p<0.05).
Our study demonstrates that ocular hypertension leads to rapid calcium-induced pericyte contraction and reduced capillary diameter, suggesting a critical role of pericytes in the regulation of the microvasculature in glaucoma. Importantly, our finding that IOP lowering does not revert pericyte-mediated capillary constriction suggests that pericytes might be an important target to restore blood flow in glaucoma.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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