Dataset Information

Retinal ischemia induces ?-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion.

ABSTRACT: Increasing evidence indicates that pericytes are vulnerable cells, playing pathophysiological roles in various neurodegenerative processes. Microvascular pericytes contract during cerebral and coronary ischemia and do not relax after re-opening of the occluded artery, causing incomplete reperfusion. However, the cellular mechanisms underlying ischemia-induced pericyte contraction, its delayed emergence, and whether it is pharmacologically reversible are unclear. Here, we investigate i) whether ischemia-induced pericyte contractions are mediated by alpha-smooth muscle actin (?-SMA), ii) the sources of calcium rise in ischemic pericytes, and iii) if peri-microvascular glycogen can support pericyte metabolism during ischemia. Thus, we examined pericyte contractility in response to retinal ischemia both in vivo, using adaptive optics scanning light ophthalmoscopy and, ex vivo, using an unbiased stereological approach. We found that microvascular constrictions were associated with increased calcium in pericytes as detected by a genetically encoded calcium indicator (NG2-GCaMP6) or a fluoroprobe (Fluo-4). Knocking down ?-SMA expression with RNA interference or fixing F-actin with phalloidin or calcium antagonist amlodipine prevented constrictions, suggesting that constrictions resulted from calcium- and ?-SMA-mediated pericyte contractions. Carbenoxolone or a Cx43-selective peptide blocker also reduced calcium rise, consistent with involvement of gap junction-mediated mechanisms in addition to voltage-gated calcium channels. Pericyte calcium increase and capillary constrictions became significant after 1?h of ischemia and were coincident with depletion of peri-microvascular glycogen, suggesting that glucose derived from glycogen granules could support pericyte metabolism and delay ischemia-induced microvascular dysfunction. Indeed, capillary constrictions emerged earlier when glycogen breakdown was pharmacologically inhibited. Constrictions persisted despite recanalization but were reversible with pericyte-relaxant adenosine administered during recanalization. Our study demonstrates that retinal ischemia, a common cause of blindness, induces ?-SMA- and calcium-mediated persistent pericyte contraction, which can be delayed by glucose driven from peri-microvascular glycogen. These findings clarify the contractile nature of capillary pericytes and identify a novel metabolic collaboration between peri-microvascular end-feet and pericytes.

SUBMITTER: Alarcon-Martinez L

PROVIDER: S-EPMC6701129 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Retinal ischemia induces α-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion.

Alarcon-Martinez Luis L Yilmaz-Ozcan Sinem S Yemisci Muge M Schallek Jesse J Kılıç Kıvılcım K Villafranca-Baughman Deborah D Can Alp A Di Polo Adriana A Dalkara Turgay T

Acta neuropathologica communications 20190820 1

Increasing evidence indicates that pericytes are vulnerable cells, playing pathophysiological roles in various neurodegenerative processes. Microvascular pericytes contract during cerebral and coronary ischemia and do not relax after re-opening of the occluded artery, causing incomplete reperfusion. However, the cellular mechanisms underlying ischemia-induced pericyte contraction, its delayed emergence, and whether it is pharmacologically reversible are unclear. Here, we investigate i) whether i ...[more]

PMID: 31429795

Similar Datasets

Project description:PurposeTo study longitudinal changes in retinal capillary circulation in eyes treated with iodine 125 (I125) plaque brachytherapy for uveal melanoma using OCT angiography (OCTA).DesignLongitudinal prospective study of 21 patients undergoing treatment for uveal melanoma with I125 plaque brachytherapy. Eyes with melanoma were imaged with OCTA before treatment and at 12-month intervals until 2 years after brachytherapy.ParticipantsAfter institutional review board approval, participants were enrolled prospectively from an academic ocular oncology clinic.MethodsPeripapillary (4.5 × 4.5-mm) and macular (3 × 3-mm) OCTA scans were acquired with AngioVue (Optovue, Inc, Fremont, CA).Main outcome measuresThe peripapillary nerve fiber layer plexus capillary density (NFLP_CD), macular superficial vascular complex vessel density (mSVC_VD), and foveal avascular zone (FAZ) area were calculated.ResultsBefore treatment, no significant difference was found in the NFLP_CD, mSVC_VD, or FAZ area between eyes with melanoma and normal fellow eyes. By 24 months, 11 eyes had developed clinical signs of radiation retinopathy, radiation optic neuropathy, or both. In treated eyes, the NFLP_CD (48.4±4.1%) was reduced at 12 months (46.7±5.0%; P = 0.04, Wilcoxon signed-rank test) and 24 months (44.5±6.1%; P < 0.001). Similarly, the mSVC_VD (48.4 2±3.6%) was reduced in treated eyes at 12 months (43.5±5.9%; P = 0.01) and 24 months (37.4±9.1%; P < 0.001). The FAZ area (0.26±0.11 mm2) increased in treated eyes at 12 months (0.35±0.22 mm2; P = 0.009) and 24 months (0.81±1.03 mm2; P = 0.001). When only eyes with clinically evident radiation changes were evaluated, the changes in NFLP_CD, mSVC_VD, and FAZ area were more pronounced. OCT angiography measurements correlated with both radiation dose and visual acuity. The mSVC_VD measured at 12 months was found to predict the development of clinically apparent radiation retinopathy within 1 year.ConclusionsOCT angiography demonstrated early emergence of peripapillary and macular capillary vasculature changes after I125 plaque brachytherapy. OCT angiography provided a quantitative measurement of retinal capillary changes associated with ischemia that correlated with visual acuity and radiation dose and may predict future development of radiation-induced retinal toxicity.

Project description:BackgroundDiabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson's disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known.MethodsWe combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood-brain barrier leakage, and the interaction between microvessels and microglia in the striatum.ResultsDifferent degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology.ConclusionThis study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.

Dataset Information

Retinal ischemia induces ?-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion.

Publications

Retinal ischemia induces α-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets